Pcna inhibitors

ABSTRACT

Described herein, inter alia, are compositions of PCNA modulators and methods for treating or preventing cancer.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/714,062, filed Dec. 13, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/760,959, filed Mar. 16, 2018, which issued asU.S. Pat. No. 10,550,070 on Feb. 4, 2020, which is a national stageapplication filed under 35 U.S.C. § 371 of International PatentApplication No. PCT/US2016/052310, filed Sep. 16, 2016, which claims thebenefit of U.S. Provisional Application No. 62/220,014 filed Sep. 17,2015, U.S. Provisional Application No. 62/313,592 filed Mar. 25, 2016,and U.S. Provisional Application No. 62/340,964 filed May 24, 2016,which are incorporated herein by reference in their entirety and for allpurposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under R01 CA121289,R01CA120954, and P30CA033572 awarded by the National Institutes ofHealth; and W81XWH-11-1-0786 awarded by the Department of Defense. Thegovernment has certain rights in the invention.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED AS AN ASCII FILE

The Sequence Listing written in file 048440-512CO₂US_ST25.TXT, createdon Nov. 20, 2020, 4,996 bytes, machine format IBM-PC, MS Windowsoperating system, is hereby incorporated by reference.

BACKGROUND

Originating from neural crest progenitor cells of the sympatheticnervous system and accounting for about 15% of all pediatric cancerdeaths, neuroblastoma (NB) is one of the most common childhood neoplasms[1]. The single most important factor determining the treatment optionsand prognosis of NB patients is risk stratification. Survival isexcellent in low and intermediate risk groups [2]. Localized perinataladrenal tumors often regress spontaneously. Current treatment forhigh-risk NB consists of induction treatment, high-dose chemotherapy andautologous stem cell transplantation (HDCT/autoSCT) as a consolidationtreatment, and maintenance treatment by 13-cis-retinoid acid andimmunotherapy to reduce relapse from minimal residual disease [3].Despite aggressive therapeutic regimens, which often cause severe sideeffects and possibly secondary malignancy [4], approximately 50% ofpatients with advanced diseases either resist treatment or relapse. Thesurvival outlook for high-risk NB patients is dismal [5, 6]. Thus, thereis a significant medical need for new therapies to improve the treatmentoutcomes of cancer. Disclosed herein are solutions to these and otherproblems in the art.

BRIEF SUMMARY

Provided herein, inter alfa, are ligands for the proliferating cellnuclear antigen (PCNA), and methods of using the same.

In an aspect is provided a compound having the formula:

wherein

Ring A is substituted or unsubstituted phenyl or substituted orunsubstituted 5 to 6 membered heteroaryl;

Ring B is substituted or unsubstituted napththyl, substituted orunsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl;

-   -   R¹ is independently a halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,        —SO₂Cl, —SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸,        —NHC═(O)NHNH₂, —NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹,        —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹,        —NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX¹ ₂, substituted or        unsubstituted alkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl; two adjacent        R¹ substituents may optionally be joined to form a substituted        or unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;

R² is independently hydrogen, halogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX² ₃, —OCHX² ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX³ ₃, —OCHX³ ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen, halogen, —CX^(A) ₃,—CHX^(A) ₂, —CH₂X^(A), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁷ and R⁸ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

z1 is independently an integer from 0 to 4;

m1 and v1 are independently 1 or 2;

n1 is independently an integer from 0 to 4;

X¹, X², X³, and X^(A) are independently —Cl, —Br, —I, or —F.

In another aspect is provided a pharmaceutical composition including acompound as described herein, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.

In another aspect is provided a method of treating cancer in a subjectin need thereof, including administering to the subject a compound asdescribed herein, or a pharmaceutically acceptable salt thereof.

In another aspect is provided a method of inhibiting PCNA activity in asubject in need thereof, including administering to the subject acompound as described herein, or a pharmaceutically acceptable saltthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1E. FIGS. 1A-1E depict data on the development of AOH1160, apotent PCNA modulator. FIG. 1A depicts the AOH1160 chemical structure.The ether oxygen in AOH1160 is indicated by a dashed box. FIG. 1B is aline graph showing that human NB cell lines, SK-N-DZ (circles), SK-N-AS(squares), and SK-N-BE(2)c (triangles tip up), were cultured in thepresence of various concentrations of AOH1160. The non-malignant 7SM0032cells (triangles tip down) and human PBMCs (crosses) were also culturedunder the same AOH1160 treatment. Cells cultured in the absence ofAOH1160 were used as control. Cell growth was measured by a CellTitorGlo assay (Promega). The average of luminescence signals in triplicatesnormalized to the control for each cell line was graphed plus/minusstandard deviations. FIG. 1C is a line graph showing TRβ reporter cellswere treated with various concentrations of T3, AOH39(N-(2-((2-benzylphenyl)amino)-2-oxoethyl)-1-naphthamide), or AOH1160 for24 h. The effect of compounds on TRβ activity was examined by measuringthe relative luminescence units (RLU) in a luminescence plate reader.Circles: Signals from T3-treated cells; squares: overlapping signalsfrom AOH39 or AOH1160-treated cells. FIG. 1D depicts a computer modelingimage of small molecule binding to PCNA. The model was initially builtby AAD methodology and further refined by 50 ns metadynamics simulation.Shown are small molecules (in stick) and PCNA surface around the bindingpocket. The loop residues of L126-Y133 of PCNA are indicated in black togray shading. The image shows AOH1160 as varying shade gray sticks andAOH39 as grey sticks. FIG. 1E depicts a series of spectra from STD NMRexperiments using 1 μM of PCNA. The T3 compound structure is shown ontop along with proton labels. Spectrum 1) is a T3 reference spectrum;spectrum 2) is the saturation spectrum of 30 μM T3 in complex with PCNAin the absence of AOH1160. Spectrum 3) is a reference spectrum of 30 μMT3 and 2.9 μM AOH116; and spectrum 4) is the saturation spectra of 30 μMT3 in complex with PCNA in the presence of 3.2 μM AOH1160.

FIGS. 2A-2D depict data on the induction of cell cycle arrest, DNAdamage, and apoptosis by AOH1160. FIG. 2A depicts a series of spectrashowing 7SM0032 (bottom series of spectra) or SK-N-DZ (top series ofspectra) cells were fixed, stained by PI, and analyzed by flow cytometryafter being treated with 500 nM AOH1160 for the indicated time. FIG. 2Bis a series of images of gels showing extracts from 7SM0032 or SK-N-DZcells treated by 500 nM AOH1160 for the indicated time were analysis bywestern analysis. FIGS. 2C-2D is a series of images showing TUNELanalysis. 7SM0032 or SK-N-DZ cells treated by 500 nM AOH1160 for 24 hwere fixed on slides. Cell apoptosis was analyzed by a TUNEL assay. FIG.2C: The TMR fluorophore attached to the free ends of DNA indicates cellsundergoing apoptosis. DAPI stained nuclei are observed. FIG. 2D: Theabundance of apoptotic cells relative to the total number of cells insix randomly selected fields were averaged and graphed plus/minusstandard deviations. The dark and light bars represent results from7SM0032 and SK-N-DZ cells respectively.

FIGS. 3A-3B. FIG. 3A depict images of individual DNA strands beingelongated from their origins of DNA replication (a DNA fiber assay), andFIG. 3B a histogram showing the inhibition of replication fork extensionby AOH1160. Synchronized cells were sequentially incubated in thepresence of CldU and IdU before and after AOH1160 treatment,respectively. Cells sequentially incubated with the same two nucleotideanalogues but without AOH1160 were used as control. Images of FIG. 3Adepict representative images of the labeled DNA strands from cellstreated with or without AOH1160. FIG. 3B depicts the lengths of CldU(light gray) and IdU (dark gray) incorporated DNA segments measured frommore than 30 independent DNA strands in cells treated with or withoutAOH1160 were averaged and graphed with standard deviations.

FIG. 4. FIG. 4 depicts a line graph showing the inhibition ofHR-mediated DSB repair. The DR-GFP (sqaures) and EJ5-GFP (circles) celllines were transiently transfected by the pCBASce plasmid that expressesthe I-SceI meganuclease. Three hours after transfection, cells weretreated with various concentrations of AOH1160 in fresh growth medium.Cells treated with DMSO were used as control. The HR (homologousrecombination) and EJ-mediated (end-joining mediated) DSB DoubleStranded Break repair events, indicated by the restoration of afunctional GFP gene in the respective cell lines, were quantified bymeasuring the relative abundance of GFP-positive cells by flowcytometry. Results in triplicates from each cell line and treatmentcondition relative to those from the control were averaged and graphedplus/minus standard deviations.

FIG. 5. FIG. 5 depicts a line graph showing the enhanced sensitivity tocisplatin by AOH1160. Human SK-N-DZ NB cells were treated with orwithout various concentrations of cisplatin (CPT) in the presence orabsence of 500 nM of AOH1160 for 18 h. Cells were washed twice withgrowth medium and were cultured in fresh medium for 3 weeks to allowcolony formation. The colony counts in dishes treated by cisplatinwithout AOH1160 (circles) were normalized to the colony counts in disheswithout cisplatin or AOH1160 treatment. The colony counts in dishestreated by both cisplatin and AOH1160 (triangles) were normalized to thecolony counts in dishes treated by 500 nM AOH1160 only. The relativenumber of colonies in triplicates for each treatment condition wereaveraged and graphed plus/minus standard deviations. * indicates p<0.01.

FIGS. 6A-6C. FIGS. 6A-6B depict measurement of the inhibition of tumorgrowth by AOH1160 in vivo. Histogram FIG. 6A depicts mice bearingSK-N-BE(2)c derived xenograft tumors that were given vehicle only or 30mg/kg of AOH1160 for 4 weeks. Tumors were isolated from these mice atthe end of the experiment. Tumor masses were measured and individuallyplotted. Circles represent mice treated with vehicle only and trianglesrepresent mice treated with AOH1160. FIG. 6B depicts animal body weightsover time. Circles represent mice treated with vehicle only andtriangles represent mice treated with AOH1160. FIG. 6C depicts Tumorvolume based on the length (L) and width (W) of the tumors (V=L×W²×0.5)at various time points after tumor implantation. Black trianglesrepresent tumor volumes from mice treated with 30 mg/kg AOH1160 andblack circles represent tumor volumes from mice treated with vehicleonly. * indicates p<0.01.

FIG. 7. NCI-60 panel test. The effect of AOH1160 on growth of the NCI-60panel, which consists of 60 cancer cell lines representing 9 majorcancer types, was tested in a 5-dose study. Shown are the Log IC50values determined for each cell line. The median IC50 for this panel ofcell lines is about 320 nM or 3.2×10⁻⁷ M (the Log value of whichcorresponds to −6.5 on the graph). This study was performed by theNational Institute of Cancer.

FIGS. 8A-8B. FIG. 8A depicts an illustration of AOH1160 degradation byamide cleavage in mouse plasma. FIG. 8B depicts the stability of AOH1160in human and animal plasma. AOH1160 was quickly degraded in the plasmacollected from a wildtype Balb/c mouse. Liquid chromatographymassspectrometry (LC-MS) analysis of AOH1160 metabolites found that thecompound was degraded by amide cleavage as illustrated in the leftpanel. This amide cleavage was catalyzed by the carboxyl esterase, ES-1,which is highly expressed in rodents, but not significantly expressed inthe blood of higher mammal species. AOH1160 is stable in the plasma ofcanine, monkey, and human, as well as in the plasma of ES-1-deficentmice (Esle/SCID). The stability of AOH1160 in Esle/SCID mice not onlyproved that ES-1 was responsible for the quick degradation of AOH1160,but also identified a mouse model which mimics the human enzymaticenvironment for pharmacological study of AOH1160.

FIG. 9. Pharmacokinetic study of AOH1160. Pharmacokinetic study isimportant to determine how much drug/compound animals actually receive.In this study, the compound was given to Esle/SCID mice orally in anewly designed formulation at 20 mg/kg. Plasmas were collected at 6 timepoints after dosing. Plasma concentration of AOH1160 was determined by

MS.

FIGS. 10A-10B. Inhibition of the growth xenograft tumor derived from atriple-negative breast cancer cell line (MDA-MB-436). Mice bearingxenograft tumors were given vehicle only or 40 mg/kg of AOH1160 throughthe study. Shown are tumor volumes (FIG. 10A) and mouse body weights(FIG. 10B) in the course of the study. The Esle/SCID mice used in thisstudy were treated by vehicle only (diamond) or by 40 mg/kg AOH1160(square) once daily. AOH1160 inhibited tumor growth, but caused nosignificant weight loss.

FIG. 11. AOH1160 stability in a liver microsome assay. Liver is a majororgan responsible for drug metabolism. We tested the stability ofAOH1160 in a liver microsome assay. By analyzing the metabolites, wedetermined a major pathway responsible for AOH1160 metabolism. AOH1160was mainly metabolized through mono- and di-hydroxylation in aNADPH-dependent manner by human liver microsomes.

FIG. 12. Effects of AOH1160 on brain tumors in mice. The compound wasgiven to tumor bearing mice once weekly. The brain cancer cells used inthis study contains a luciferase. For measuring tumor growth, luciferinwas injected into each mouse. The relative growth of the tumors in livemice was determined by measuring luminescent signals by a CCD camera.The compound inhibited brain tumor growth.

FIGS. 13A-13F. Identification of AOH1996, a stable analog of AOH1160.Since AOH1160 were found to be metabolized mainly through hydroxylationin liver, we synthesized several AOH1160 analogs, some of which mimichydroxylated AOH1160 (FIG. 13B and 13C). Other analogs have thecorresponding hydroxylated sites blocked by o-methylation (FIG. 13D and13E). One o-methylated analog, AOH1996, is stable to NADPH dependentmetabolism in a liver microsome assay (FIG. 13F).

FIGS. 14A-14B: Like AOH1160, AOH1996 selectively kills neuroblastoma(FIG. 14A) and small cell lung cancer cells (FIG. 14B) at belowmicromolar concentrations. This compound has minimal toxicity tonon-malignant cells, including neural crest stem cells (7SM0032), humansmall airway epithelial cells (hSAEC), and PBMCs.

FIGS. 15A-15C. Like AOH1160, AOH1996 caused S/G2 cell cycle arrest inneuroblastoma cells (SH-SYSY and SK-N-BE(2)c), but exerted little effecton normal cells (7SM0032).

DETAILED DESCRIPTION

Proliferating cell nuclear antigen (PCNA) plays an essential role inregulating DNA synthesis and repair and is indispensible to cancer cellgrowth and survival. Previously a novel cancer associated PCNA isoform(dubbed caPCNA), which was ubiquitously expressed in a broad range ofcancer cells and tumor tissues, but not significantly in non-malignantcells was reported. It was found that the caPCNA-specific antigenic sitelies between L126 and Y133 inside the interdomain connecting loop ofPCNA. By computer modeling and medicinal chemistry targeting a bindingpocket partly delineated by the L126-Y133 region of PCNA, AOH1160, apotent PCNA inhibitor, which selectively kills neuroblastoma (NB) cellswithout significant toxicity to a broad range of non-malignant cells wasidentified. Mechanistically, AOH1160 interferes with DNA replication,blocks homologous recombination mediated DNA repair, and causes cellcycle arrest. It induces apoptosis in NB cells and sensitizes them tocisplatin treatment. AOH1160 is orally available to animals andsuppresses tumor growth without causing death or significant weight lossin mice. These results illustrate the favorable pharmacological andtherapeutic properties of AOH1160 and demonstrate its potential as anovel therapeutic agent for treating NB.

PCNA lies at the center of essential cellular processes, including DNAreplication, cell cycle control, and DNA damage repair [10], which arefundamental to the proliferation and survival of cancer cells.Inhibition of PCNA is viewed as an effective way to suppress tumorgrowth and several attempts have been made in recent years to blockvarious aspects of PCNA function [13, 19, 39-42]. Distinctions instructure and accessibility in the L126-Y133 region between nmPCNA andcaPCNA [16] and studies showing that the cell permeable peptidecontaining the L126-Y133 octapeptide can block PCNA interaction with itsinteracting partners and selectively kill NB cells without causingsignificant toxicity to non-malignant cells [18], the L126-Y133 regionon PCNA is an attractive target.

Described herein is the successful identification of small moleculecompounds that inhibit PCNA function, including AOH1160. The compound ischemically novel in the drug discovery space. AOH1160 has especiallyremarkable favorable therapeutic properties. AOH1160 is a small moleculePCNA inhibitor that is orally available and kills tumors in vivo withoutcausing significant toxicity after being systematically administrated toanimals. Therefore, successful translation of this compound into theclinic may lead to a new class of anti-cancer drug and significantlyimprove NB treatment options. In addition to the potential of AOH1160 asan effective monotherapeutic agent, its ability to sensitize NB cells totreatment by DNA damaging agents (e.g., platinum containing compounds)may significantly improve the efficacy and reduce the dose-limitingside-effects of traditional chemotherapies in the clinic.

A. DEFINITIONS

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchednon-cyclic carbon chain (or carbon), or combination thereof, which maybe fully saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example,n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkylgroup is one having one or more double bonds or triple bonds. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. An alkoxy is an alkyl attached to theremainder of the molecule via an oxygen linker (—O—). An alkyl moietymay be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. Analkyl moiety may be fully saturated.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms. Theterm “alkenylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched non-cyclicchain, or combinations thereof, including at least one carbon atom andat least one heteroatom (e.g., O, N, P, Si, or S), and wherein thenitrogen and sulfur atoms may optionally be oxidized, and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N,P, S, or Si) may be placed at any interior position of the heteroalkylgroup or at the position at which the alkyl group is attached to theremainder of the molecule. Examples include, but are not limited to:—CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up totwo or three heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃ and CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include oneheteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includetwo optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include three optionally different heteroatoms(e.g., O, N, S, Si, or P). A heteroalkyl moiety may include fouroptionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include five optionally different heteroatoms(e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8optionally different heteroatoms (e.g., O, N, S, Si, or P).

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated,non-aromatic cyclic versions of “alkyl” and “heteroalkyl,” respectively,wherein the carbons making up the ring or rings do not necessarily needto be bonded to a hydrogen due to all carbon valencies participating inbonds with non-hydrogen atoms. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,3-hydroxy-cyclobut-3-enyl-1,2, dione, 1H-1,2,4-triazolyl-5(4H)-one,4H-1,2,4-triazolyl, and the like. Examples of heterocycloalkyl include,but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a “heterocycloalkylene,” alone or as part of anothersubstituent, means a divalent radical derived from a cycloalkyl andheterocycloalkyl, respectively. A heterocycloalkyl moiety may includeone ring heteroatom (e.g., O, N, S, Si, or P). A heterocycloalkyl moietymay include two optionally different ring heteroatoms (e.g., O, N, S,Si, or P). A heterocycloalkyl moiety may include three optionallydifferent ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkylmoiety may include four optionally different ring heteroatoms (e.g., O,N, S, Si, or P). A heterocycloalkyl moiety may include five optionallydifferent ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkylmoiety may include up to 8 optionally different ring heteroatoms (e.g.,O, N, S, Si, or P).

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl.

Substituents for each of the above noted aryl and heteroaryl ringsystems are selected from the group of acceptable substituents describedbelow. An “arylene” and a “heteroarylene,” alone or as part of anothersubstituent, mean a divalent radical derived from an aryl andheteroaryl, respectively. Non-limiting examples of aryl and heteroarylgroups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl,indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl,pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl,quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl,benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl,pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl,furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl,benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl,diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl,pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl,or quinolyl. The examples above may be substituted or unsubstituted anddivalent radicals of each heteroaryl example above are non-limitingexamples of heteroarylene. A heteroaryl moiety may include one ringheteroatom (e.g., O, N, or S). A heteroaryl moiety may include twooptionally different ring heteroatoms (e.g., O, N, or S). A heteroarylmoiety may include three optionally different ring heteroatoms (e.g., O,N, or S). A heteroaryl moiety may include four optionally different ringheteroatoms (e.g., O, N, or S). A heteroaryl moiety may include fiveoptionally different ring heteroatoms (e.g., O, N, or S). An aryl moietymay have a single ring. An aryl moiety may have two optionally differentrings. An aryl moiety may have three optionally different rings. An arylmoiety may have four optionally different rings. A heteroaryl moiety mayhave one ring. A heteroaryl moiety may have two optionally differentrings. A heteroaryl moiety may have three optionally different rings. Aheteroaryl moiety may have four optionally different rings. A heteroarylmoiety may have five optionally different rings.

A fused ring heterocyloalkyl-aryl is an aryl fused to aheterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is aheteroaryl fused to a heterocycloalkyl. A fused ringheterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkylfused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl,fused ring heterocycloalkyl-heteroaryl, fused ringheterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substitutentsdescribed herein.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is a substituted or unsubstituted alkylgroup as defined above. R′ may have a specified number of carbons (e.g.,“C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,”, “cycloalkyl”,“heterocycloalkyl”, “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)N R′R″,—NR″C (O)R′, —NR′—C(O)NR″R″′, —NR″C (O)₂R′, —NR—C(NR′R″R″′)═NR″″,—NR—C(NR′R″)═NR″′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, NR′NR″R″′,ONR′R″, —NR′C═(O)NR″NR″′R″″, —CN, —NO₂, in a number ranging from zero to(2m′+1), where m′ is the total number of carbon atoms in such radical.R, R′, R″, R″′, and R″″ each preferably independently refer to hydrogen,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R″′,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC (O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″, —NR—C(NR′ R″)═NR″′,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′, —ONR′R″,NR′C═(O)NR″NR″′R″′, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the totalnumber of open valences on the aromatic ring system; and where R′, R″,R″′, and R″″ are preferably independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R″′, and R″″ groupswhen more than one of these groups is present.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3.

Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O) —, —S(O)₂—, —S(O)₂NR′—, or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X′—(C″R″)_(d)—, where s and d are independently integers offrom 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″, and R″′ are preferably independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,        —SH, —SO₃H, —SO₄H, —SO₂NH₂, NHNH₂, ONH₂, NHC═(O)NHNH₂, NHC═(O)        NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,        unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted        cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,        unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,            —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,            —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃,            —OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl,                unsubstituted heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, heteroaryl, substituted with at least one                substituent selected from: oxo,            -   halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,                —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,                —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,                —OCF₃, —OCHF₂, unsubstituted alkyl, unsubstituted                heteroalkyl, unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl.

A “size-limited substituent” or “ size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “ lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19(1977)). Certain specific compounds of the present invention containboth basic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts. Otherpharmaceutically acceptable carriers known to those of skill in the artare suitable for the present invention. Salts tend to be more soluble inaqueous or other protonic solvents than are the corresponding free baseforms. In other cases, the preparation may be a lyophilized powder in 1mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5to 5.5, that is combined with buffer prior to use.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Provided herein are agents (e.g. compounds, drugs, therapeutic agents)that may be in a prodrug form. Prodrugs of the compounds describedherein are those compounds that readily undergo chemical changes underselect physiological conditions to provide the final agents (e.g.compounds, drugs, therapeutic agents). Additionally, prodrugs can beconverted to agents (e.g. compounds, drugs, therapeutic agents) bychemical or biochemical methods in an ex vivo environment. Prodrugsdescribed herein include compounds that readily undergo chemical changesunder select physiological conditions to provide agents (e.g. compounds,drugs, therapeutic agents) to a biological system (e.g. in a subject, ina cancer cell, in the extracellular space near a cancer cell).

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as(R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomersare encompassed within the scope of the present invention. The compoundsof the present invention do not include those which are known in the artto be too unstable to synthesize and/or isolate. The present inventionis meant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The terms “a” or “an,” as used herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls. Moreover, where a moiety is substitutedwith an R substituent, the group may be referred to as “R-substituted.”Where a moiety is R-substituted, the moiety is substituted with at leastone R substituent and each R substituent is optionally different.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,certain methods herein treat diseases associated with PCNA activity.Certain methods described herein may treat diseases associated with PCNAactivity (e.g., cancer or neuroblastoma) by inhibiting PCNA activity.For example, certain methods herein treat cancer. For example certainmethods herein treat cancer by decreasing a symptom of cancer. Symptomsof cancer would be known or may be determined by a person of ordinaryskill in the art. The term “treating” and conjugations thereof, includeprevention of an injury, pathology, condition, or disease.

An “effective amount” is an amount sufficient to accomplish a statedpurpose (e.g. achieve the effect for which it is administered, treat adisease, reduce enzyme activity, increase enzyme activity, reduceprotein function, reduce one or more symptoms of a disease orcondition). An example of an “effective amount” is an amount sufficientto contribute to the treatment, prevention, or reduction of a symptom orsymptoms of a disease, which could also be referred to as a“therapeutically effective amount.” A “reduction” of a symptom orsymptoms (and grammatical equivalents of this phrase) means decreasingof the severity or frequency of the symptom(s), or elimination of thesymptom(s). A “prophylactically effective amount” of a drug or prodrugis an amount of a drug or prodrug that, when administered to a subject,will have the intended prophylactic effect, e.g., preventing or delayingthe onset (or reoccurrence) of an injury, disease, pathology orcondition, or reducing the likelihood of the onset (or reoccurrence) ofan injury, disease, pathology, or condition, or their symptoms. The fullprophylactic effect does not necessarily occur by administration of onedose, and may occur only after administration of a series of doses.Thus, a prophylactically effective amount may be administered in one ormore administrations. The exact amounts will depend on the purpose ofthe treatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g.cancer) means that the disease is caused by (in whole or in part), or asymptom of the disease is caused by (in whole or in part) the substanceor substance activity or function. As used herein, what is described asbeing associated with a disease, if a causative agent, could be a targetfor treatment of the disease. For example, a disease associated withPCNA activity may be treated with an agent (e.g. compound as describedherein) effective for decreasing the level of PCNA activity.

“Control” or “control experiment” or “standard control” is used inaccordance with its plain ordinary meaning and refers to an experimentin which the subjects or reagents of the experiment are treated as in aparallel experiment except for omission of a procedure, reagent, orvariable of the experiment. In some instances, the control is used as astandard of comparison in evaluating experimental effects. Inembodiments, a control is the same experiment or treatment method in theabsence of a compound (e.g., as described herein) used in thenon-control experiment or treatment method being compared to thecontrol.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules, or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated, however, that the resulting reaction product can beproduced directly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture. The term “contacting” may includeallowing two species to react, interact, or physically touch, whereinthe two species may be a compound as described herein and a protein orenzyme. In some embodiments contacting includes allowing a compounddescribed herein to interact with a protein (e.g., PCNA) or enzyme. Inembodiments contacting includes allowing a compound described herein tointeract with SEQ ID NO:2. In embodiments contacting includes allowing acompound described herein to interact with SEQ ID NO:3. In embodimentscontacting includes allowing a compound described herein to interactwith SEQ ID NO:4.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor (e.g. antagonist)interaction means negatively affecting (e.g. decreasing) the level ofactivity or function of the protein relative to the level of activity orfunction of the protein in the absence of the inhibitor. In someembodiments inhibition refers to reduction of a disease or symptoms ofdisease. Thus, inhibition may include, at least in part, partially ortotally blocking stimulation, decreasing, preventing, or delayingactivation, or inactivating, desensitizing, or down-regulating signaltransduction or enzymatic activity or the amount of a protein.

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein-activator (e.g. agonist) interactionmeans positively affecting (e.g. increasing) the activity or function ofthe protein relative to the activity or function of the protein in theabsence of the activator (e.g. compound described herein). Thus,activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein decreased in a disease.Activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein.

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule. Inembodiments, a modulator is an anti-cancer agent. In embodiments, amodulator is a PCNA antagonist. In embodiments, a modulator is a PCNAinhibitor.

“Anti-cancer agent” or “anti-cancer drug” is used in accordance with itsplain ordinary meaning and refers to a composition (e.g. compound, drug,antagonist, inhibitor, modulator) having antineoplastic properties orthe ability to inhibit the growth or proliferation of cells. In someembodiments, an anti-cancer agent is a chemotherapeutic. In someembodiments, an anti-cancer agent is an agent approved by the FDA orsimilar regulatory agency of a country other than the USA, for treatingcancer. Examples of anti-cancer agents include, but are not limited to,anti-androgens (e.g., Casodex, Flutamide, MDV3100, or ARN-509), MEK(e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040,PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973,ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733,PD318088, AS703026, BAY 869766), alkylating agents (e.g.,cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards(e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan),ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa),alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,lomusitne, semustine, streptozocin), triazenes (decarbazine)),anti-metabolites (e.g., 5-azathioprine, leucovorin, capecitabine,fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog(e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine,vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel,docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan,amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.),antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin,epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin,etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin,carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea(e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),adrenocortical suppressant (e.g., mitotane, aminoglutethimide),epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin,doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors ofmitogen-activated protein kinase signaling (e.g. U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002), mTOR inhibitors, antibodies (e.g., rituxan),5-aza-2′-deoxycytidine, doxorubicin, vincristine, etoposide,gemcitabine, imatinib (Gleevec.®.), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), bortezomib,trastuzumab, anastrozole; angiogenesis inhibitors; antiandrogen,antiestrogen; antisense oligonucleotides; apoptosis gene modulators;apoptosis regulators; arginine deaminase; BCR/ABL antagonists; betalactam derivatives; bFGF inhibitor; bicalutamide; camptothecinderivatives; casein kinase inhibitors (ICOS); clomifene analogues;cytarabine dacliximab; dexamethasone; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;finasteride; fludarabine; fluorodaunorunicin hydrochloride; gadoliniumtexaphyrin; gallium nitrate; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; immunostimulant peptides;insulin-like growth factor-1 receptor inhibitor; interferon agonists;interferons; interleukins; letrozole; leukemia inhibiting factor;leukocyte alpha interferon; leuprolide+estrogen+progesterone;leuprorelin; matrilysin inhibitors; matrix metalloproteinase inhibitors;MIF inhibitor; mifepristone; mismatched double stranded RNA; monoclonalantibody,; mycobacterial cell wall extract; nitric oxide modulators;oxaliplatin; panomifene; pentrozole; phosphatase inhibitors; plasminogenactivator inhibitor; platinum complex; platinum compounds; prednisone;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein tyrosine phosphatase inhibitors; purine nucleosidephosphorylase inhibitors; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; ribozymes; signal transductioninhibitors; signal transduction modulators; single chain antigen-bindingprotein; stem cell inhibitor; stem-cell division inhibitors; stromelysininhibitors; synthetic glycosaminoglycans; tamoxifen methiodide;telomerase inhibitors; thyroid stimulating hormone; translationinhibitors; tyrosine kinase inhibitors; urokinase receptor antagonists;steroids (e.g., dexamethasone), finasteride, aromatase inhibitors,gonadotropin-releasing hormone agonists (GnRH) such as goserelin orleuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In ⁹⁰Y or ¹³¹I,etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin,epirubicin, topotecan, itraconazole, vindesine, cerivastatin,vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan,clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib,gefitinib, EGFR inhibitors, epidermal growth factor receptor(EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™),erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™),panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992,CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306,ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethylerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002,WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib,sunitinib, dasatinib, pyrrolo benzodiazepines (e.g. tomaymycin),carboplatin, CC-1065 and CC-1065 analogs including amino-CBIs, nitrogenmustards (such as chlorambucil and melphalan), dolastatin and dolastatinanalogs (including auristatins: eg. monomethyl auristatin E),anthracycline antibiotics (such as doxorubicin, daunorubicin, etc.),duocarmycins and duocarmycin analogs, enediynes (such asneocarzinostatin and calicheamicins), leptomycin derivaties,maytansinoids and maytansinoid analogs (e.g. mertansine), methotrexate,mitomycin C, taxoids, vinca alkaloids (such as vinblastine andvincristine), epothilones (e.g. epothilone B), camptothecin and itsclinical analogs topotecan and irinotecan, or the like.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordancewith its plain ordinary meaning and refers to a chemical composition orcompound having antineoplastic properties or the ability to inhibit thegrowth or proliferation of cells.

“Patient” or “subject in need thereof” or “subject” refers to a livingorganism suffering from or prone to a disease or condition that can betreated by administration of a compound or pharmaceutical composition orby a method, as provided herein. Non-limiting examples include humans,other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows,deer, and other non-mammalian animals. In some embodiments, a patient ishuman. In some embodiments, a subject is human. In some embodiments, asubject is a human child (e.g., less than 18, 17, 16, 15, 14, 13, 12,11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 years of age).

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with a compound,pharmaceutical composition, or method provided herein. In someembodiments, the disease is a disease having the symptom of cellhyperproliferation. In some embodiments, the disease is a disease havingthe symptom of an aberrant level of PCNA activity. In some embodiments,the disease is a cancer. In some further instances, “cancer” refers tohuman cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas,leukemias, etc., including solid and lymphoid cancers, kidney, breast,lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, headand neck, skin, uterine, testicular, glioma, esophagus, and livercancer, including hepatocarcinoma, lymphoma, including B-acutelymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, SmallCell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (includingAML, ALL, and CML), or multiple myeloma. In embodiments, the disease isbrain cancer. In embodiments, the disease is neuroblastoma. Inembodiments, the disease is glioblastoma. In embodiments, the disease isa central nervous system (CNS) cancer. In embodiments, the disease is asympathetic nervous system (SNS) cancer. In embodiments, the disease isan adrenal gland cancer. In embodiments, the disease is a cancer of aneuron in the neck, chest, abdomen, or pelvis. In embodiments, thedisease is an esthesioneuroblastoma. In embodiments, the disease is astage 1 neuroblastoma (e.g., localized tumor confined to an area nearthe origin). In embodiments, the disease is a a stage 2A neuroblastoma(e.g., Unilateral tumor with incomplete gross resection and/oridentifiable ipsilateral and contralateral lymph node negative fortumor). In embodiments, the disease is a a stage 2B neuroblastoma (e.g.,Unilateral tumor with complete or incomplete gross resection; withipsilateral lymph node positive for tumor; identifiable contralaterallymph node negative for tumor). In embodiments, the disease is a a stage3 neuroblastoma (e.g., Tumor infiltrating across midline with or withoutregional lymph node involvement; or unilateral tumor with contralaterallymph node involvement; or midline tumor with bilateral lymph nodeinvolvement). In embodiments, the disease is a a stage 4 neuroblastoma(e.g., Dissemination of tumor to distant lymph nodes, bone marrow, bone,liver, or other organs except as defined by Stage 4S). In embodiments,the disease is a a stage 4S neuroblastoma (e.g., Age <1 year old withlocalized primary tumor as described in Stage 1 or Stage 2 above, withdissemination limited to liver, skin, or bone marrow (less than 10percent of nucleated bone marrow cells are tumors). In embodiments, thedisease is a stage L1 neuroblastoma (e.g., localized disease withoutimage-defined risk factors) according to the International NeuroblastomaRisk Group (INRG) staging system. In embodiments, the disease is a stageL2 neuroblastoma (e.g., localized disease with image-defined riskfactors) according to the International Neuroblastoma Risk Group (INRG)staging system. In embodiments, the disease is a stage M neuroblastoma(e.g., metastatic disease) according to the International NeuroblastomaRisk Group (INRG) staging system. In embodiments, the disease is a stageMS neuroblastoma (e.g., metastatic disease “special” where MS isequivalent to stage 4S as described above) according to theInternational Neuroblastoma Risk Group (INRG) staging system. Inembodiments, the disease is a neuroblastoma risk stratificationpre-treatment group, according to the International Neuroblastoma RiskGroup (INRG) staging system, of very low. In embodiments, the disease isa neuroblastoma risk stratification pre-treatment group, according tothe International Neuroblastoma Risk Group (INRG) staging system, oflow. In embodiments, the disease is a neuroblastoma risk stratificationpre-treatment group, according to the International Neuroblastoma RiskGroup (INRG) staging system, of intermediate. In embodiments, thedisease is a neuroblastoma risk stratification pre-treatment group,according to the International Neuroblastoma Risk Group (INRG) stagingsystem, of high risk.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals (e.g. humans), includingleukemia, carcinomas and sarcomas. Exemplary cancers that may be treatedwith a compound or method provided herein include cancer of theprostate, thyroid, endocrine system, brain, breast, cervix, colon, head& neck, liver, kidney, lung, non-small cell lung, melanoma,mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma,colorectal cancer, pancreatic cancer. Additional examples may include,Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,primary brain tumors, cancer, malignant pancreatic insulanoma, malignantcarcinoid, urinary bladder cancer, premalignant skin lesions, testicularcancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer,genitourinary tract cancer, malignant hypercalcemia, endometrial cancer,adrenal cortical cancer, neoplasms of the endocrine or exocrinepancreas, medullary thyroid cancer, medullary thyroid carcinoma,melanoma, colorectal cancer, papillary thyroid cancer, hepatocellularcarcinoma, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, medullarythyroid carcinoma, familial medullary thyroid carcinoma, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propagated to other signaling pathway components.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity, aberrant refers to activity that isgreater or less than a normal control or the average of normalnon-diseased control samples. Aberrant activity may refer to an amountof activity that results in a disease, wherein returning the aberrantactivity to a normal or non-disease-associated amount (e.g. byadministering a compound or using a method as described herein), resultsin reduction of the disease or one or more disease symptoms.

“Nucleic acid” or “oligonucleotide” or “polynucleotide” or grammaticalequivalents used herein means at least two nucleotides covalently linkedtogether. The term “nucleic acid” includes single-, double-, ormultiple-stranded DNA, RNA and analogs (derivatives) thereof.Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25,30, 40, 50 or more nucleotides in length, up to about 100 nucleotides inlength. Nucleic acids and polynucleotides are a polymers of any length,including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000,7000, 10,000, etc. Nucleic acids containing one or more carbocyclicsugars are also included within one definition of nucleic acids.

A particular nucleic acid sequence also encompasses “splice variants.”Similarly, a particular protein encoded by a nucleic acid encompassesany protein encoded by a splice variant of that nucleic acid. “Splicevariants,” as the name suggests, are products of alternative splicing ofa gene. After transcription, an initial nucleic acid transcript may bespliced such that different (alternate) nucleic acid splice productsencode different polypeptides. Mechanisms for the production of splicevariants vary, but include alternate splicing of exons. Alternatepolypeptides derived from the same nucleic acid by read-throughtranscription are also encompassed by this definition. Any products of asplicing reaction, including recombinant forms of the splice products,are included in this definition.

Nucleic acid is “operably linked” when it is placed into a functionalrelationship with another nucleic acid sequence. For example, DNA for apresequence or secretory leader is operably linked to DNA for apolypeptide if it is expressed as a preprotein that participates in thesecretion of the polypeptide; a promoter or enhancer is operably linkedto a coding sequence if it affects the transcription of the sequence; ora ribosome binding site is operably linked to a coding sequence if it ispositioned so as to facilitate translation. Generally, “operably linked”means that the DNA sequences being linked are near each other, and, inthe case of a secretory leader, contiguous and in reading phase.However, enhancers do not have to be contiguous. Linking is accomplishedby ligation at convenient restriction sites. If such sites do not exist,the synthetic oligonucleotide adaptors or linkers are used in accordancewith conventional practice.

The terms “identical” or percent “identity,” in the context of two ormore nucleic acids or polypeptide sequences, refer to two or moresequences or subsequences that are the same or have a specifiedpercentage of amino acid residues or nucleotides that are the same(i.e., about 60% identity, preferably 61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% ,94%, 95%,96%, 97%, 98%, 99% or higher identity over a specified region whencompared and aligned for maximum correspondence over a comparison windowor designated region) as measured using a BLAST or BLAST 2.0 sequencecomparison algorithms with default parameters described below, or bymanual alignment and visual inspection (see, e.g., NCBI web site or thelike). Such sequences are then said to be “substantially identical.”This definition also refers to, or may be applied to, the compliment ofa test sequence. The definition also includes sequences that havedeletions and/or additions, as well as those that have substitutions. Asdescribed below, the preferred algorithms can account for gaps and thelike. Preferably, identity exists over a region that is at least about10 amino acids or 20 nucleotides in length, or more preferably over aregion that is 10-50 amino acids or 20-50 nucleotides in length. As usedherein, percent (%) amino acid sequence identity is defined as thepercentage of amino acids in a candidate sequence that are identical tothe amino acids in a reference sequence, after aligning the sequencesand introducing gaps, if necessary, to achieve the maximum percentsequence identity. Alignment for purposes of determining percentsequence identity can be achieved in various ways that are within theskill in the art, for instance, using publicly available computersoftware such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR)software. Appropriate parameters for measuring alignment, including anyalgorithms needed to achieve maximal alignment over the full-length ofthe sequences being compared can be determined by known methods.

For sequence comparisons, typically one sequence acts as a referencesequence, to which test sequences are compared. When using a sequencecomparison algorithm, test and reference sequences are entered into acomputer, subsequence coordinates are designated, if necessary, andsequence algorithm program parameters are designated. Preferably,default program parameters can be used, or alternative parameters can bedesignated. The sequence comparison algorithm then calculates thepercent sequence identities for the test sequences relative to thereference sequence, based on the program parameters.

A “comparison window”, as used herein, includes reference to a segmentof any one of the number of contiguous positions selected from the groupconsisting of from 10 to 600, usually about 50 to about 200, moreusually about 100 to about 150 in which a sequence may be compared to areference sequence of the same number of contiguous positions after thetwo sequences are optimally aligned. Methods of alignment of sequencesfor comparison are well-known in the art. Optimal alignment of sequencesfor comparison can be conducted, e.g., by the local homology algorithmof Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homologyalignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970),by the search for similarity method of Pearson & Lipman, Proc. Nat'l.Acad. Sci. USA 85:2444 (1988), by computerized implementations of thesealgorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin GeneticsSoftware Package, Genetics Computer Group, 575 Science Dr., Madison,Wis.), or by manual alignment and visual inspection (see, e.g., CurrentProtocols in Molecular Biology (Ausubel et al., eds. 1995 supplement)).

The phrase “selectively (or specifically) hybridizes to” refers to thebinding, duplexing, or hybridizing of a molecule only to a particularnucleotide sequence with a higher affinity, e.g., under more stringentconditions, than to other nucleotide sequences (e.g., total cellular orlibrary DNA or RNA).

The phrase “stringent hybridization conditions” refers to conditionsunder which a probe will hybridize to its target subsequence, typicallyin a complex mixture of nucleic acids, but to no other sequences.Stringent conditions are sequence-dependent and will be different indifferent circumstances. Longer sequences hybridize specifically athigher temperatures. An extensive guide to the hybridization of nucleicacids is found in Tijssen, Techniques in Biochemistry and MolecularBiology—Hybridization with Nucleic Probes, “Overview of principles ofhybridization and the strategy of nucleic acid assays” (1993).Generally, stringent conditions are selected to be about 5-10° C. lowerthan the thermal melting point (T_(m)) for the specific sequence at adefined ionic strength pH. The T_(m) is the temperature (under definedionic strength, pH, and nucleic concentration) at which 50% of theprobes complementary to the target hybridize to the target sequence atequilibrium (as the target sequences are present in excess, at T_(m),50% of the probes are occupied at equilibrium). Stringent conditions mayalso be achieved with the addition of destabilizing agents such asformamide. For selective or specific hybridization, a positive signal isat least two times background, preferably 10 times backgroundhybridization. Exemplary stringent hybridization conditions can be asfollowing: 50% formamide, 5× SSC, and 1% SDS, incubating at 42° C., or,5× SSC, 1% SDS, incubating at 65° C., with wash in 0.2× SSC, and 0.1%SDS at 65° C.

Nucleic acids that do not hybridize to each other under stringentconditions are still substantially identical if the polypeptides whichthey encode are substantially identical. This occurs, for example, whena copy of a nucleic acid is created using the maximum codon degeneracypermitted by the genetic code. In such cases, the nucleic acidstypically hybridize under moderately stringent hybridization conditions.Exemplary “moderately stringent hybridization conditions” include ahybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37° C.,and a wash in 1× SSC at 45° C. A positive hybridization is at leasttwice background. Those of ordinary skill will readily recognize thatalternative hybridization and wash conditions can be utilized to provideconditions of similar stringency. Additional guidelines for determininghybridization parameters are provided in numerous reference, e.g., andCurrent Protocols in Molecular Biology, ed. Ausubel, et al.

Twenty amino acids are commonly found in proteins. Those amino acids canbe grouped into nine classes or groups based on the chemical propertiesof their side chains. Substitution of one amino acid residue for anotherwithin the same class or group is referred to herein as a “conservative”substitution. Conservative amino acid substitutions can frequently bemade in a protein without significantly altering the conformation orfunction of the protein. Substitution of one amino acid residue foranother from a different class or group is referred to herein as a“non-conservative” substitution. In contrast, non-conservative aminoacid substitutions tend to modify conformation and function of aprotein.

Example of Amino Acid Classification

-   Small/Aliphatic residues: Gly, Ala, Val, Leu, Ile-   Cyclic Imino Acid: Pro-   Hydroxyl-containing Residues: Ser, Thr-   Acidic Residues: Asp, Glu-   Amide Residues: Asn, Gln-   Basic Residues: Lys, Arg-   Imidazole Residue: His-   Aromatic Residues: Phe, Tyr, Trp-   Sulfur-containing Residues: Met, Cys

In some embodiments, the conservative amino acid substitution comprisessubstituting any of glycine (G), alanine (A), isoleucine (I), valine(V), and leucine (L) for any other of these aliphatic amino acids;serine (S) for threonine (T) and vice versa; aspartic acid (D) forglutamic acid (E) and vice versa; glutamine (Q) for asparagine (N) andvice versa; lysine (K) for arginine (R) and vice versa; phenylalanine(F), tyrosine (Y) and tryptophan (W) for any other of these aromaticamino acids; and methionine (M) for cysteine (C) and vice versa. Othersubstitutions can also be considered conservative, depending on theenvironment of the particular amino acid and its role in thethree-dimensional structure of the protein. For example, glycine (G) andalanine (A) can frequently be interchangeable, as can alanine (A) andvaline (V). Methionine (M), which is relatively hydrophobic, canfrequently be interchanged with leucine and isoleucine, and sometimeswith valine. Lysine (K) and arginine (R) are frequently interchangeablein locations in which the significant feature of the amino acid residueis its charge and the differing pKs of these two amino acid residues arenot significant. Still other changes can be considered “conservative” inparticular environments (see, e.g., BIOCHEMISTRY at pp. 13-15, 2nd ed.Lubert Stryer ed. (Stanford University); Henikoff et al., Proc. Nat'lAcad. Sci. USA (1992) 89:10915-10919; Lei et al., J. Biol. Chem. (1995)270(20):11882-11886).

“Polypeptide,” “peptide,” and “protein” are used herein interchangeablyand mean any peptide-linked chain of amino acids, regardless of lengthor post-translational modification. As noted below, the polypeptidesdescribed herein can be, e.g., wild-type proteins, biologically-activefragments of the wild-type proteins, or variants of the wild-typeproteins or fragments. Variants, in accordance with the disclosure, cancontain amino acid substitutions, deletions, or insertions. Thesubstitutions can be conservative or non-conservative.

Following expression, the proteins can be isolated. The term “purified”or “isolated” as applied to any of the proteins described herein refersto a polypeptide that has been separated or purified from components(e.g., proteins or other naturally-occurring biological or organicmolecules) which naturally accompany it, e.g., other proteins, lipids,and nucleic acid in a cell expressing the proteins. Typically, apolypeptide is purified when it constitutes at least 60 (e.g., at least65, 70, 75, 80, 85, 90, 92, 95, 97, or 99) %, by weight, of the totalprotein in a sample.

An amino acid residue in a protein “corresponds” to a given residue whenit occupies the same essential structural position within the protein asthe given residue. For example, a selected residue in a selected proteincorresponds to L126 to Y133 of human PCNA when the selected residueoccupies the same essential spatial or other structural relationship asL126 to Y133 in human PCNA. In some embodiments, where a selectedprotein is aligned for maximum homology with the human PCNA protein, theposition in the aligned selected protein aligning with L126 to Y133 issaid to correspond to L126 to Y133. Instead of a primary sequencealignment, a three dimensional structural alignment can also be used,e.g., where the structure of the selected protein is aligned for maximumcorrespondence with the human PCNA protein and the overall structurescompared. In this case, an amino acid that occupies the same essentialposition as L126 to Y133 in the structural model is said to correspondto the L126 to Y133 residues.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intracranial, intranasal or subcutaneous administration, or theimplantation of a slow-release device, e.g., a mini-osmotic pump, to asubject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal,vaginal, rectal, or transdermal). Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc. By“co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies (e.g. anti-canceragent). The compound of the invention can be administered alone or canbe coadministered to the patient. Coadministration is meant to includesimultaneous or sequential administration of the compound individuallyor in combination (more than one compound or agent). Thus, thepreparations can also be combined, when desired, with other activesubstances (e.g. to reduce metabolic degradation, to increasedegradation of a prodrug and release of the drug, detectable agent). Thecompositions of the present invention can be delivered by transdermally,by a topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols. Oral preparations include tablets, pills,powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups,slurries, suspensions, etc., suitable for ingestion by the patient.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. Liquid formpreparations include solutions, suspensions, and emulsions, for example,water or water/propylene glycol solutions. The compositions of thepresent invention may additionally include components to providesustained release and/or comfort. Such components include high molecularweight, anionic mucomimetic polymers, gelling polysaccharides andfinely-divided drug carrier substrates. These components are discussedin greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and4,861,760. The entire contents of these patents are incorporated hereinby reference in their entirety for all purposes. The compositions of thepresent invention can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions of the present invention can alsobe delivered as nanoparticles.

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient (e.g. compounds describedherein, including embodiments or examples) is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alfa, on the condition beingtreated. When administered in methods to treat a disease, suchcompositions will contain an amount of active ingredient effective toachieve the desired result, e.g., reducing, eliminating, or slowing theprogression of disease symptoms (e.g. symptoms of cancer or aberrantPCNA activity). Determination of a therapeutically effective amount of acompound of the invention is well within the capabilities of thoseskilled in the art, especially in light of the detailed disclosureherein.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated (e.g. symptoms of cancer), kind of concurrent treatment,complications from the disease being treated or other health-relatedproblems. Other therapeutic regimens or agents can be used inconjunction with the methods and compounds of Applicants' invention.Adjustment and manipulation of established dosages (e.g., frequency andduration) are well within the ability of those skilled in the art.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating cancer,or with adjunctive agents that may not be effective alone, but maycontribute to the efficacy of the active agent.

In some embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a secondactive agent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both active agents. In other embodiments, the active agentscan be formulated separately. In another embodiment, the active and/oradjunctive agents may be linked or conjugated to one another. In someembodiments, the compounds described herein may be combined withtreatments for cancer such as radiation or surgery.

As used herein, the term “about” means a range of values including thespecified value, which a person of ordinary skill in the art wouldconsider reasonably similar to the specified value. In embodiments,about means within a standard deviation using measurements generallyacceptable in the art. In embodiments, about means a range extending to+/−10% of the specified value. In embodiments, about means the specifiedvalue.

The term “Proliferating cell nuclear antigen” or “PCNA” refers to an 29kDa protein that self assembles into a protein complex consisting of 3subunits of individual PCNA proteins. Together these joined PCNAmolecules form a DNA clamp that acts as a processivity factor for DNApolymerase 6 in eukaryotic cells. The term “PCNA” may refer to thenucleotide sequence or protein sequence of human PCNA (e.g., Entrez5111, Uniprot P12004, RefSeq NM_002592 (SEQ ID NO:1), or RefSeqNP_002583 (SEQ ID NO:2)). The term “PCNA” includes both the wild-typeform of the nucleotide sequences or proteins as well as any mutantsthereof. In some embodiments, “PCNA” is wild-type PCNA. In someembodiments, “PCNA” is one or more mutant forms. The term “PCNA” XYZrefers to a nucleotide sequence or protein of a mutant PCNA wherein theY numbered amino acid of PCNA that normally has an X amino acid in thewild-type, instead has a Z amino acid in the mutant. In embodiments, aPCNA is the human PCNA. In embodiments, the PCNA has the nucleotidesequence corresponding to reference number GI:33239449 (SEQ ID NO:1). Inembodiments, the PCNA has the nucleotide sequence corresponding toRefSeq NM_002592.2 (SEQ ID NO:1). In embodiments, the PCNA has theprotein sequence corresponding to reference number GI:4505641 (SEQ IDNO:2). In embodiments, the PCNA has the nucleotide sequencecorresponding to RefSeq NP_002583.1 (SEQ ID NO:2). In embodiments, thePCNA has the following amino acid sequence:

(SEQ ID NO: 2) MFEARLVQGSILKKVLEALKDLINEACWDISSSGVNLQSMDSSHVSLVQLTLRSEGFDTYRCDRNLAMGVNLTSMSKILKCAGNEDIITLRAEDNADTLALVFEAPNQEKVSDYEMKLMDLDVEQLGIPEQEYSCVVKMPSGEFARICRDLSHIGDAVVISCAKDGVKFSASGELGNGNIKLSQTSNVDKEEEAVTIEMNEPVQLTFALRYLNFFTKATPLSSTVTLSMSADVPLVVEYKIADMG HLKYYLAPKIEDEEGS.

In embodiments, the PCNA is a mutant PCNA. In embodiments, the mutantPCNA is associated with a disease that is not associated with wild-typePCNA. In embodiments, the PCNA includes at least one amino acid mutation(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared tothe sequence above. PCNA may be post-translationally modified.Modifications may include phosphorylation, methylation, methylesters ofacidic amino acids, ribosylation, acetylation, glycosylation with avariety of sugars, lipidation with a variety of different lipids,poly(ADP) ribosylation, or other post-translational modifications knownin the art. Differences in the extent and type of modificationinfluences the levels (e.g., protein levels) of the ca- and nm-PCNAisoforms. In embodiments, a post-translational modification or pluralityof post-translational modifications modify the inhibition of PCNA by acompound described herein (e.g., AOH1160, PCNA7) or the binding of acompound described herein (e.g., AOH1160, PCNA7) to PCNA, relative toPCNA without the post-translational modification(s).

The terms “cancer-associated Proliferating cell nuclear antigen” or“caPCNA” as used herein refer to an isoform of PCNA having an acidicisoelectric point (e.g., peptide including protonated amine and/orcarboxyl groups, acidic isoelectric point compared to anon-cancer-associated PCNA, PCNA in non-cancerous cells, non-malignantPCNA, prevalent PCNA isoform in non-cancerous cells, or less acidic PCNAisoform in non-cancerous cells). In embodiments, the caPCNA proteinincludes methylated amino acids (e.g., glutamate, aspartic acid). Inembodiments, the caPCNA protein is post-translationally modified with amethylester of an acidic amino acid. In embodiments, themethylesterification of the acidic amino acid residues on PCNA exhibit aT_(1/2) of approximately 20 minutes at pH 8.5. In embodiments, caPCNA ispost-translationally modified as described in F. Shen, et al. J CellBiochem. 2011 March; 112(3): 756-760, which is incorporated by referencein its entirety for all purposes.

The terms “non-malignant Proliferating cell nuclear antigen” or “nmPCNA”as used herein refer to an isoform of PCNA having a basic isoelectricpoint (e.g., peptide including deprotonated amine and/or carboxylgroups, basic isoelectric point compared to a caPCNA, caPCNA incancerous cells). In embodiments, nmPCNA is the prevalent PCNA isoformin non-cancerous cells.

B. COMPOUNDS

Provided herein, inter alfa, are compositions of a compound, or apharmaceutically acceptable salt thereof, having the formula:

Ring A is a substituted or unsubstituted phenyl or a substituted orunsubstituted 5 to 6 membered heteroaryl. Ring B is a substituted orunsubstituted napththyl, a substituted or unsubstituted quinolinyl, or asubstituted or unsubstituted isoquinolinyl.

R¹ is independently hydrogen, halogen, —CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN,—SO₂Cl, —SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸, —NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸,—NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸,—OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX¹₂, —OCH₂X¹, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; twoadjacent R¹ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R¹ is independently a halogen,—CX¹ ₃, —CHX¹ ₂, —CH₂X¹, —CN, —SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸, —NHNH₂,—ONR⁷R⁸, —NHC═(O)NHNH₂, —NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹,—C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)—OR⁹,—NR⁷OR⁹, —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; twoadjacent R¹ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. It is understood that when z1 is 0, then R¹ ishydrogen.

R² is independently hydrogen, halogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX² ₃, —OCHX² ₂, —OCH₂X², substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX³ ₃, —OCHX³ ₂, —OCH₂X³, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen, halogen, —CX^(A) ₃,—CHX^(A) ₂, —CH₂X^(A), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, —OCH₂X^(A),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁷ and R⁸ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl.

The symbol z1 is an integer from 0 to 4. The symbols m1 and v1 areindependently an integer 1 or 2. The symbol n1 is an integer from 0 to4. The symbols X¹, X², X³, and X^(A) are independently —Cl, —Br, —I, or—F.

In embodiments, the compound has the formula:

R¹, R², R³, Ring A, Ring B, and z1 are as described herein, including incompounds of formula (I) and including in embodiments. In embodiments,Ring A is phenyl (substituted or unsubstituted with R⁴) or 5 to 6membered heteroaryl (substituted or unsubstituted with R⁴) and Ring B isnapththyl (substituted or unsubstituted with R⁵), quinolinyl(substituted or unsubstituted with R⁵), or isoquinolinyl (substituted orunsubstituted with R⁵).

R⁴ is independently halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —SO₂Cl,—SO_(n4)R¹⁴, —SO_(v4)NR¹¹R¹², —NHNR¹¹R¹², —ONR¹¹R¹², —NHC═(O)NHNR¹¹R¹²,—NHC═(O)NR¹¹R¹², —N(O)_(m4), —NR¹¹R¹², —C(O)R¹³, —C(O)—OR¹³,—C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³, —NR¹¹C(O)—OR¹³,—NR¹¹OR¹³, —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; two adjacent R⁴ substituents may optionally be joined toform a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R⁴ isindependently a halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —SO_(n4)R¹⁴,—SO_(v4)NR¹¹R¹², —NHNR¹¹R¹², —ONR¹¹R¹², —NHC═(O)NHNR¹¹R¹²,—NHC═(O)NR¹¹R¹², —N(O)_(m4), —NR¹¹R¹², —C(O)R¹³, —C(O)—OR¹³,—C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³, —NR¹¹—C(O)—OR¹³,—NR¹¹OR¹³, —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; two adjacent R⁴ substituents may optionally be joined toform a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. It is understood that when z2is 0, then R⁴ is hydrogen.

R⁵ is independently halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —SO₂Cl,—SO_(n5)R¹⁸, —SO_(v5)NR¹⁵R¹⁶, —NHNR¹⁵R¹⁶, —ONR¹⁵R¹⁶, —NHC═(O)NHNR¹⁵R¹⁶,—NHC═(O)NR¹⁵R¹⁶, —N(O)_(m5), —NR¹⁵R¹⁶, —C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶, —OR¹⁸,—NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX⁵ ₃, —OCHX⁵₂, —OCH₂X⁵, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; twoadjacent R⁵ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R⁵ is independently a halogen,—CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —SO_(n5)R¹⁸, —SO_(v5)NR¹⁵R¹⁶, —NHNR¹⁵R¹⁶,—ONR¹⁵R¹⁶, —NHC═(O)NHNR¹⁵R¹⁶, —NHC═(O)NR¹⁵R¹⁶, —N(O)_(m5), —NR¹⁵R¹⁶,—C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶, —OR¹⁸, —NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷,—NR¹⁵C(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX⁵ ₃, —OCHX⁵ ₂, —OCH₂X⁵, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R⁵ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. It is understood that when z3is 0, then R⁵ is hydrogen,

R¹¹, R¹², R¹³, and R¹⁴ are independently hydrogen, halogen, —CX^(B) ₃,—CHX^(B) ₂, —CH₂X^(B), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX^(B) ₃, —OCHX^(B) ₂, —OCH₂X^(B),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹ and R¹² substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl.

R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independently hydrogen, halogen, —CX^(C) ₃,—CHX^(C) ₂, —CH₂X^(C), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NH H₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX^(C) ₃, —OCHX^(C) ₂, —OCH₂X^(C),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹⁵ and R¹⁶ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl.

The symbol z2 is an integer from 0 to 5. The symbol z3 is an integerfrom 0 to 7. The symbols m4, m5, v4 and v5 are independently an integer1 or 2. The symbols n4 and n5 are independently an integer from 0 to 4.The symbols X⁴, X⁵, X^(B), and X^(C) are independently —Cl, —Br, —I, orF.

In embodiments, Ring A is substituted phenyl. In embodiments, Ring A isunsubstituted phenyl. In embodiments, Ring A is phenyl. In embodiments,Ring A is a substituted 5 to 6 membered heteroaryl. In embodiments, RingA is an unsubstituted 5 to 6 membered heteroaryl. In embodiments, Ring Ais a 5 to 6 membered heteroaryl. In embodiments, Ring A is a substitutedthienyl. In embodiments, Ring A is an unsubstituted thienyl. Inembodiments, Ring A is a thienyl. In embodiments, Ring A is a 2-thienyl.In embodiments, Ring A is a 3-thienyl. In embodiments, Ring A is asubstituted pyridyl. In embodiments, Ring A is an unsubstituted pyridyl.In embodiments, Ring A is a pyridyl. In embodiments, Ring A is a2-pyridyl. In embodiments, Ring A is a 3-pyridyl. In embodiments, Ring Ais a 4-pyridyl. In embodiments, Ring Ais unsubstituted pyrrolyl. Inembodiments, Ring A is substituted pyrrolyl. In embodiments, Ring Aispyrrolyl. In embodiments, Ring A is unsubstituted furanyl. Inembodiments, Ring Ais substituted furanyl. In embodiments, Ring A isfuranyl. In embodiments, Ring A is unsubstituted pyrazolyl. Inembodiments, Ring A is substituted pyrazolyl. In embodiments, Ring Aispyrazolyl. In embodiments, Ring A is unsubstituted imidazolyl. Inembodiments, Ring A is substituted imidazolyl. In embodiments, Ring A isimidazolyl. In embodiments, Ring A is unsubstituted oxazolyl. Inembodiments, Ring A is substituted oxazolyl. In embodiments, Ring A isoxazolyl. In embodiments, Ring A is unsubstituted isoxazolyl. Inembodiments, Ring A is substituted isoxazolyl. In embodiments, Ring A isisoxazolyl. In embodiments, Ring A is unsubstituted thiazolyl. Inembodiments, Ring A is substituted thiazolyl. In embodiments, Ring A isthiazolyl. In embodiments, Ring A is unsubstituted triazolyl. Inembodiments, Ring A is substituted triazolyl. In embodiments, Ring A istriazolyl. In embodiments, Ring B is a substituted napththyl. Inembodiments, Ring B is unsubstituted napththyl. In embodiments, Ring Bis a napththyl. In embodiments, Ring B is a 1-napththyl. In embodiments,Ring B is a 2-napththyl. In embodiments, Ring B is a quinolinyl. Inembodiments, Ring B is a substituted quinolinyl. In embodiments, Ring Bis unsubstituted quinolinyl. In embodiments, Ring B is an isoquinolinyl.In embodiments, Ring B is a substituted isoquinolinyl. In embodiments,Ring B is unsubstituted isoquinolinyl. In embodiments, Ring B is a1-isoquinolinyl. In embodiments, Ring B is a 3-isoquinolinyl. Inembodiments, Ring B is a 4-isoquinolinyl.

In embodiments, R¹ is independently halogen, —CF₃, —CHF₂, —OCF₃, —OCHF₂,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstituted 2to 8 membered heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R¹ is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹ isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R¹ isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R¹ is independently halogen. In embodiments, R¹is independently —CF₃. In embodiments, R¹ is independently —CHF₂. Inembodiments, R¹ is independently —CH₂F. In embodiments, R¹ isindependently —OCF₃. In embodiments, R¹ is independently —OCHF₂. Inembodiments, R¹ is independently —OCH₂F. In embodiments, R¹ isindependently substituted or unsubstituted C₁-C₈ alkyl. In embodiments,le is independently substituted or unsubstituted 2 to 8 memberedheteroalkyl. In embodiments, le is independently substituted orunsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹ is independentlysubstituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, le is independently substituted or unsubstituted C₆-C₁₀aryl. In embodiments, R¹ is independently substituted or unsubstituted 5to 10 membered heteroaryl. In embodiments, R¹ is independently —OH. Inembodiments, R¹ is independently —NH₂. In embodiments, R¹ isindependently —SH. In embodiments, R¹ is independently substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R¹ is independentlysubstituted or unsubstituted 2 to 4 membered heteroalkyl. Inembodiments, R¹ is independently substituted or unsubstituted C₃-C₆cycloalkyl. In embodiments, R¹ is independently substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R¹ isindependently substituted or unsubstituted phenyl. In embodiments, R¹ isindependently substituted or unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R¹ is independently substituted C₁-C₈ alkyl. Inembodiments, R¹ is independently substituted 2 to 8 memberedheteroalkyl. In embodiments, R¹ is independently substituted C₃-C₈cycloalkyl. In embodiments, R¹ is independently substituted 3 to 8membered heterocycloalkyl. In embodiments, R¹ is independentlysubstituted C₆-C₁₀ aryl. In embodiments, le is independently substituted5 to 10 membered heteroaryl. In embodiments, R¹ is independentlysubstituted C₁-C₄ alkyl. In embodiments, R¹ is independently substitutedto 4 membered heteroalkyl. In embodiments, R¹ is independentlysubstituted C₃-C₆ cycloalkyl. In embodiments, R¹ is independentlysubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R¹ isindependently substituted phenyl. In embodiments, R¹ is independentlysubstituted 5 to 6 membered heteroaryl. In embodiments, R¹ isindependently unsubstituted C₁-C₈ alkyl. In embodiments, R¹ isindependently unsubstituted 2 to 8 membered heteroalkyl. In embodiments,R¹ is independently unsubstituted C₃-C₈ cycloalkyl. In embodiments, R¹is independently unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R¹ is independently unsubstituted C₆-C₁₀ aryl. Inembodiments, R¹ is independently unsubstituted 5 to 10 memberedheteroaryl. In embodiments, R¹ is independently unsubstituted C₁-C₄alkyl. In embodiments, R¹ is independently unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R¹ is independently unsubstituted C₃-C₆cycloalkyl. In embodiments, R¹ is independently unsubstituted 3 to 6membered heterocycloalkyl. In embodiments, R¹ is independentlyunsubstituted phenyl. In embodiments, R¹ is independently unsubstituted5 to 6 membered heteroaryl. In embodiments, R¹ is independentlyunsubstituted methyl. In embodiments, R¹ is independently unsubstitutedethyl. In embodiments, R¹ is independently unsubstituted isopropyl. Inembodiments, R¹ is independently unsubstituted tert-butyl. Inembodiments, R¹ is independently unsubstituted methoxy. In embodiments,R¹ is independently unsubstituted ethoxy. In embodiments, R¹ isindependently —F. In embodiments, R¹ is independently —Cl. Inembodiments, R¹ is independently —Br. In embodiments, R¹ isindependently —I. In embodiments, R¹ is independently hydrogen. Inembodiments, R¹ is independently halogen, —CF₃, CHF₂, —CH₂F, —OCF₃,—OCHF₂, —OCH₂F, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl.

In embodiments, z1 is 1. In embodiments, z1 is 0. In embodiments, z1 is2. In embodiments, z1 is 3. In embodiments, z1 is 4.

In embodiments, R² is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X²,—CN, —C(O)H, —C(O)OH, —C(O)NH₂, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl,substituted or unsubstituted C₃-C₆ cycloalkyl, substituted orunsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments R² is independently hydrogen, unsubstitutedmethyl, unsubstituted ethyl, or unsubstituted isopropyl. In embodiments,R² is independently hydrogen. In embodiments, R² is independentlyunsubstituted methyl. In embodiments, R² is independently unsubstitutedethyl.

In embodiments, R² is independently unsubstituted isopropyl. Inembodiments, R² is independently unsubstituted tert-butyl.

In embodiments, R² is independently hydrogen, halogen, —CX² ₃, —CHX² ₂,—CH₂X², —CN, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R³ is independently hydrogen, —CX² ₃, —CHX² ₂, —CH₂X²,—CN, —C(O)H, —C(O)OH, —C(O)NH₂, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl,substituted or unsubstituted C₃-C₆ cycloalkyl, substituted orunsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R³ is independently hydrogen, unsubstitutedmethyl, unsubstituted ethyl, or unsubstituted isopropyl. In embodiments,R³ is independently hydrogen. In embodiments, R³ is independentlyunsubstituted methyl. In embodiments, R³ is independently unsubstitutedethyl.

In embodiments, R³ is independently unsubstituted isopropyl. Inembodiments, R³ is independently unsubstituted tert-butyl. Inembodiments, R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂,—CH₂X³, —CN, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R⁴ is independently halogen, —CF₃, CHF₂, —CH₂F, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —OCF₃, —OCHF₂, —OCH₂F, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted 2 to 8membered heteroalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted 3 to 8 membered heterocycloalkyl,substituted or unsubstituted C₆-C₁₀ aryl, or substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, R⁴ isindependently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R⁴ is independently halogen, —OH, —NH₂, —SH,unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.In embodiments, R⁴ is independently halogen, —OH, unsubstituted methyl,or unsubstituted methoxy. In embodiments, R⁴ is independently halogen.In embodiments, R⁴ is independently —OH. In embodiments, R⁴ isindependently unsubstituted methyl. In embodiments, R⁴ is independentlyunsubstituted methoxy. In embodiments, R⁴ is independently unsubstitutedethyl. In embodiments, R⁴ is independently —F. In embodiments, R⁴ isindependently —Cl. In embodiments, R⁴ is independently —Br. Inembodiments, R⁴ is independently —I. In embodiments, R⁴ is independently—CF₃. In embodiments, R⁴ is independently —NH₂. In embodiments, R⁴ isindependently —SH. In embodiments, R⁴ is independently unsubstitutedisopropyl. In embodiments, R⁴ is independently unsubstituted tert-butyl.In embodiments, R⁴ is independently unsubstituted ethoxy. Inembodiments, R⁴ is independently unsubstituted propoxy.

In embodiments, R⁴ is independently a halogen. In embodiments, R⁴ isindependently —CX⁴3. In embodiments, R⁴ is independently —CHX⁴2. Inembodiments, R⁴ is independently —CH₂X⁴. In embodiments, R⁴ isindependently —CN. In embodiments, R⁴ is independently —SO_(n4)R¹⁴. Inembodiments, R⁴ is independently —SR¹⁴. In embodiments, R⁴ isindependently —SO_(v4)NR¹¹R¹². In embodiments, R⁴ is independently—NHNR¹¹R¹². In embodiments, R⁴ is independently —ONR¹¹R¹². Inembodiments, R⁴ is independently —NHC═(O)NHNR¹¹R¹². In embodiments, R⁴is independently —NHC═(O)NR¹¹R¹². In embodiments, R⁴ is independently—N(O)_(m4). In embodiments, R⁴ is independently —NR¹¹R¹². Inembodiments, R⁴ is independently —C(O)R¹³. In embodiments, R⁴ isindependently —C(O)—OR¹³. In embodiments, R⁴ is independently—C(O)NR¹¹R¹². In embodiments, R⁴ is independently —OR¹⁴. In embodiments,R⁴ is independently —NR¹¹SO₂R¹⁴. In embodiments, R⁴ is independently—NR¹¹C═(O)R¹³. In embodiments, R⁴ is independently —NR¹¹C(O)—OR¹³. Inembodiments, R⁴ is independently —NR¹¹OR¹³. In embodiments, R⁴ isindependently —OCX⁴ ₃. In embodiments, R⁴ is independently —OCHX⁴ ₂. Inembodiments, R⁴ is independently —OCH₂X⁴. In embodiments, R⁴ isindependently —CF₃. In embodiments, R⁴ is independently —CHF₂. Inembodiments, R⁴ is independently —CH₂F. In embodiments, R⁴ isindependently —SO₂CH₃. In embodiments, R⁴ is independently —SO₂NH₂. Inembodiments, R⁴ is independently —SH. In embodiments, R⁴ isindependently —N(O)₂. In embodiments, R⁴ is independently —NH₂. Inembodiments, R⁴ is independently —C(O)CH₃. In embodiments, R⁴ isindependently —C(O)OH. In embodiments, R⁴ is independently —C(O)NH₂. Inembodiments, R⁴ is independently —OH. In embodiments, R⁴ isindependently —OCF₃. In embodiments, R⁴ is independently —OCHF₂. Inembodiments, R⁴ is independently —OCH₂F.

In embodiments, R⁴ is independently halogen, —CF₃, CHF₂, —CH₂F, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —OCF₃, —OCHF₂, —OCH₂F, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted 2 to 8membered heteroalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted 3 to 8 membered heterocycloalkyl,substituted or unsubstituted C₆-C₁₀ aryl, or substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, R⁴ isindependently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R⁴ is independently halogen, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl,or unsubstituted 2 to 4 membered heteroalkyl.

In embodiments, R⁴ is independently substituted or unsubstituted alkyl.In embodiments, R⁴ is independently substituted or unsubstitutedheteroalkyl. In embodiments, R⁴ is independently substituted orunsubstituted cycloalkyl. In embodiments, R⁴ is independentlysubstituted or unsubstituted heterocycloalkyl. In embodiments, R⁴ isindependently substituted or unsubstituted aryl. In embodiments, R⁴ isindependently substituted or unsubstituted heteroaryl. In embodiments,two adjacent R⁴ substituents may optionally be joined to form asubstituted or unsubstituted cycloalkyl. In embodiments, two adjacent R⁴substituents may optionally be joined to form a substituted orunsubstituted heterocycloalkyl. In embodiments, two adjacent R⁴substituents may optionally be joined to form a substituted orunsubstituted aryl. In embodiments, two adjacent R⁴ substituents mayoptionally be joined to form a substituted or unsubstituted heteroaryl.

In embodiments, R⁴ is independently substituted or unsubstituted alkyl(e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.C₆-C₁₀ aryl or C₆ aryl), or substituted or unsubstituted heteroaryl(e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁴ is independently substitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substitutedheteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 memberedheteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl,or 2 to 4 membered heteroalkyl), substituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), substitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted aryl(e.g. C₆-C₁₀ aryl or C₆ aryl), or substituted heteroaryl (e.g. 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R⁴ is independently unsubstituted alkyl(e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 memberedheteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl,or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstitutedaryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or unsubstituted heteroaryl (e.g. 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl).

In embodiments, R¹⁴ is independently hydrogen, —CX^(B) ₃, —CHX^(B) ₂,—CH₂X^(B), —CN, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R¹⁴ is independently hydrogen. In embodiments, R¹⁴ isindependently —CX^(B) ₃. In embodiments, R¹⁴ is independently —CHX^(B)₂. In embodiments, R¹⁴ is independently —CH₂X^(B). In embodiments, R¹⁴is independently —CN. In embodiments, R¹⁴ is independently —COOH. Inembodiments, R¹⁴ is independently —CONH₂. In embodiments, R¹⁴ isindependently substituted or unsubstituted alkyl. In embodiments, R¹⁴ isindependently substituted or unsubstituted heteroalkyl. In embodiments,R¹⁴ is independently substituted or unsubstituted cycloalkyl. Inembodiments, R¹⁴ is independently substituted or unsubstitutedheterocycloalkyl. In embodiments, R¹⁴ is independently substituted orunsubstituted aryl. In embodiments, R¹⁴ is independently substituted orunsubstituted heteroaryl. In embodiments, R¹⁴ is independentlysubstituted alkyl. In embodiments, R¹⁴ is independently substitutedheteroalkyl. In embodiments, R¹⁴ is independently substitutedcycloalkyl. In embodiments, R¹⁴ is independently substitutedheterocycloalkyl. In embodiments, R¹⁴ is independently substituted aryl.In embodiments, R¹⁴ is independently substituted heteroaryl. Inembodiments, R¹⁴ is independently unsubstituted alkyl. In embodiments,R¹⁴ is independently unsubstituted heteroalkyl. In embodiments, R¹⁴ isindependently unsubstituted cycloalkyl. In embodiments, R¹⁴ isindependently unsubstituted heterocycloalkyl. In embodiments, R¹⁴ isindependently unsubstituted aryl. In embodiments, R¹⁴ is independentlyunsubstituted heteroaryl. In embodiments, R¹⁴ is independentlysubstituted or unsubstituted C₁-C₄ alkyl. In embodiments, R¹⁴ isindependently substituted or unsubstituted 2 to 4 membered heteroalkyl.In embodiments, R¹⁴ is independently substituted or unsubstituted C₃-C₆cycloalkyl. In embodiments, R¹⁴ is independently substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R¹⁴ isindependently substituted or unsubstituted phenyl. In embodiments, R¹⁴is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹⁴ is independently substituted C₁-C₄alkyl. In embodiments, R¹⁴ is independently substituted 2 to 4 memberedheteroalkyl. In embodiments, R¹⁴ is independently substituted C₃-C₆cycloalkyl. In embodiments, R¹⁴ is independently substituted 3 to 6membered heterocycloalkyl. In embodiments, R¹⁴ is independentlysubstituted phenyl. In embodiments, R¹⁴ is independently substituted 5to 6 membered heteroaryl. In embodiments, R¹⁴ is independentlyunsubstituted C₁-C₄ alkyl. In embodiments, R¹⁴ is independentlyunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R¹⁴ isindependently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R¹⁴ isindependently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹⁴ is independently unsubstituted phenyl. In embodiments,R¹⁴ is independently unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R¹⁴ ishydrogen or unsubstituted methyl.

In embodiments, R¹⁴ is substituted or unsubstituted pyrazolyl. Inembodiments, R¹⁴ is substituted or unsubstituted pyridyl. Inembodiments, R¹⁴ is substituted or unsubstituted imidazolyl. Inembodiments, R¹⁴ is substituted or unsubstituted oxazolyl. Inembodiments, R¹⁴ is substituted or unsubstituted isoxazolyl. Inembodiments, R¹⁴ is substituted or unsubstituted thiazolyl. Inembodiments, R¹⁴ is substituted or unsubstituted furanyl. Inembodiments, R¹⁴ is substituted or unsubstituted pyrrolyl. Inembodiments, R¹⁴ is substituted or unsubstituted thienyl. Inembodiments, R¹⁴ is substituted pyrazolyl. In embodiments, R¹⁴ issubstituted pyridyl. In embodiments, R¹⁴ is substituted imidazolyl. Inembodiments, R¹⁴ is substituted oxazolyl. In embodiments, R¹⁴ issubstituted isoxazolyl. In embodiments, R¹⁴ issubstituted thiazolyl. Inembodiments, R¹⁴ is substituted furanyl. In embodiments, R¹⁴issubstituted pyrrolyl. In embodiments, R¹⁴ is substituted thienyl. Inembodiments, R¹⁴ is unsubstituted pyrazolyl. In embodiments, R¹⁴ isunsubstituted pyridyl. In embodiments, R¹⁴ isunsubstituted imidazolyl.In embodiments, R¹⁴ is unsubstituted oxazolyl. In embodiments, R¹⁴isunsubstituted isoxazolyl. In embodiments, R¹⁴ is unsubstitutedthiazolyl. In embodiments, R¹⁴ is unsubstituted furanyl. In embodiments,R¹⁴ is unsubstituted pyrrolyl. In embodiments, R¹⁴ is unsubstitutedthienyl.

In embodiments, R¹⁴ is independently hydrogen or unsubstituted alkyl. Inembodiments, R¹⁴ is independently hydrogen or unsubstituted C₁-C₆ alkyl.In embodiments, R¹⁴ is independently hydrogen or unsubstituted C₁-C₅alkyl. In embodiments, R¹⁴ is independently hydrogen or unsubstitutedC₁-C₄ alkyl. In embodiments, R¹⁴ is independently hydrogen orunsubstituted C₁-C₃ alkyl. In embodiments, R¹⁴ is independently hydrogenor unsubstituted C₁-C₂ alkyl. In embodiments, R¹⁴ is independentlyhydrogen or unsubstituted C₂-C₆ alkyl. In embodiments, R¹⁴ isindependently hydrogen or unsubstituted C₂-C₅ alkyl. In embodiments, R¹⁴is independently hydrogen or unsubstituted C₂-C₄ alkyl. In embodiments,R¹⁴ is independently hydrogen or unsubstituted C₂-C₃ alkyl. Inembodiments, R¹⁴ is independently hydrogen or unsubstituted C₃-C₆ alkyl.In embodiments, R¹⁴ is independently hydrogen or unsubstituted C₄-C₆alkyl. In embodiments, R¹⁴ is independently hydrogen or unsubstitutedC₅-C₆ alkyl. In embodiments, R¹⁴ is independently hydrogen. Inembodiments, R¹⁴ is independently unsubstituted alkyl. In embodiments,R¹⁴ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₁-C₅ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₁-C₃ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₁-C₂ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₂-C₆ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₂-C₅ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₂-C₄ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₂-C₃ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₃-C₆ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₄-C₆ alkyl. In embodiments, R¹⁴ isindependently unsubstituted C₅-C₆ alkyl. In embodiments, R¹⁴ isindependently —CF₃. In embodiments, R¹⁴ is independently CHF₂. Inembodiments, R¹⁴ is independently —CH₂F. In embodiments, R¹⁴ isindependently —CCl₃. In embodiments, R¹⁴ is independently —CHCl₂. Inembodiments, R¹⁴ is independently —CH₂Cl. In embodiments, R¹⁴ isindependently —CBr₃. In embodiments, R¹⁴ is independently —CHBr₂. Inembodiments, R¹⁴ is independently —CH₂Br. In embodiments, R¹⁴ isindependently —CI₃. In embodiments, R¹⁴ is independently —CHI₂. Inembodiments, R¹⁴ is independently CH₂I. In embodiments, R¹⁴ isindependently unsubstituted C₁-C₄ haloalkyl. In embodiments, R¹⁴ isindependently unsubstituted C₁-C₃ haloalkyl. In embodiments, R¹⁴ isindependently unsubstituted C₁-C₂ haloalkyl. In embodiments, R¹⁴ isindependently unsubstituted C₂-C₆ haloalkyl. In embodiments, R¹⁴ isindependently unsubstituted C₂-C₅ haloalkyl. In embodiments, R¹⁴ isindependently unsubstituted C₂-C₄ haloalkyl. In embodiments, R¹⁴ isindependently unsubstituted C₂-C₃ haloalkyl. In embodiments, R¹⁴ isindependently unsubstituted methyl. In embodiments, R¹⁴ is independentlyunsubstituted ethyl. In embodiments, R¹⁴ is independently unsubstitutedpropyl. In embodiments, R¹⁴ is independently unsubstituted isopropyl. Inembodiments, R¹⁴ is independently unsubstituted butyl. In embodiments,R¹⁴ is independently unsubstituted isobutyl. In embodiments, R¹⁴ isindependently unsubstituted tert-butyl.

In embodiments, z2 is 1. In embodiments, z2 is 0. In embodiments, z2 is2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2is 5.

In embodiments, R⁵ is independently halogen, —CF₃, —CHF₂, —CH₂F, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —OCF₃, —OCHF₂, —OCH₂F, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted 2 to 8membered heteroalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted 3 to 8 membered heterocycloalkyl,substituted or unsubstituted C₆-C₁₀ aryl, or substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, R⁵ isindependently halogen, —CF₃, —CHF₂, —CH₂F, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —OCF₃, —OCHF₂, —OCH₂F, substituted or unsubstitutedC₁-C₈ alkyl or substituted or unsubstituted 2 to 8 membered heteroalkyl.

In embodiments, R⁵ is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁵ isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R⁵ isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R⁵ is independently halogen. In embodiments, R⁵is independently —OH. In embodiments, R⁵ is independently unsubstitutedmethyl. In embodiments, R⁵ is independently unsubstituted methoxy. Inembodiments, R⁵ is independently unsubstituted ethyl. In embodiments, R⁵is independently —F. In embodiments, R⁵ is independently —Cl. Inembodiments, R⁵ is independently —Br. In embodiments, R⁵ isindependently —I. In embodiments, R⁵ is independently —CF₃. Inembodiments, R⁵ is independently —NH₂. In embodiments, R⁵ isindependently —SH. In embodiments, R⁵ is independently unsubstitutedisopropyl. In embodiments, R⁵ is independently unsubstituted tert-butyl.In embodiments, R⁵ is independently unsubstituted ethoxy. Inembodiments, R⁵ is independently unsubstituted propoxy.

In embodiments, R⁵ is independently substituted or unsubstituted alkyl(e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), substituted or unsubstituted aryl (e.g.C₆-C₁₀ aryl or C₆ aryl), or substituted or unsubstituted heteroaryl(e.g. 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁵ is independently substitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), substitutedheteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 memberedheteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl,or 2 to 4 membered heteroalkyl), substituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), substitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), substituted aryl(e.g. C₆-C₁₀ aryl or C₆ aryl), or substituted heteroaryl (e.g. 5 to 10membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 memberedheteroaryl). In embodiments, R⁵ is independently unsubstituted alkyl(e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstitutedheteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 memberedheteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl,or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), unsubstitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstitutedaryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or unsubstituted heteroaryl (e.g. 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R⁵ is independently halogen, —CF₃,—CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OH, —NH₂, —SH, unsubstituted C₁-C₄alkyl, or unsubstituted 2 to 4 membered heteroalkyl. In embodiments, R⁵is unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R⁵ is unsubstituted C₁-C₄ alkyl. Inembodiments, R⁵ is unsubstituted 2 to 4 membered heteroalkyl.

In embodiments, R⁵ is independently unsubstituted alkyl. In embodiments,R⁵ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R⁵ isindependently unsubstituted C₁-C₅ alkyl. In embodiments, R⁵ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁵ isindependently unsubstituted C₁-C₃ alkyl. In embodiments, R⁵ isindependently unsubstituted C₁-C₂ alkyl. In embodiments, R⁵ isindependently unsubstituted C₂-C₆ alkyl. In embodiments, R⁵ isindependently unsubstituted C₂-C₅ alkyl. In embodiments, R⁵ isindependently unsubstituted C₂-C₄ alkyl. In embodiments, R⁵ isindependently unsubstituted C₂-C₃ alkyl. In embodiments, R⁵ isindependently unsubstituted C₃-C₆ alkyl. In embodiments, R⁵ isindependently unsubstituted C₄-C₆ alkyl. In embodiments, R⁵ isindependently unsubstituted C₅-C₆ alkyl.

In embodiments, z3 is 1. In embodiments, z3 is 0. In embodiments, z3 is2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3is 5. In embodiments, z3 is 6. In embodiments, z3 is 7.

In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independently hydrogen, —CX^(B)₃, —CHX^(B) ₂, —CH₂X^(B), —CN, —COOH, —CONH₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently hydrogen. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently —CX^(B)3. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently —CHX^(B) ₂. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently —CH₂X^(B). In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently —CN. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently —COOH. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently —CONH₂. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently substituted or unsubstituted alkyl. In embodiments, R¹¹,R¹², R¹³, or R¹⁴ is independently substituted or unsubstitutedheteroalkyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, R¹¹, R¹², R¹³,or R¹⁴ is independently substituted or unsubstituted heterocycloalkyl.In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independently substituted orunsubstituted aryl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently substituted or unsubstituted heteroaryl. In embodiments,R¹¹, R¹², R¹³, or R¹⁴ is independently substituted alkyl. Inembodiments, R¹¹, R¹², R¹³, or R¹⁴ is independently substitutedheteroalkyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independentlysubstituted cycloalkyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently substituted heterocycloalkyl.

In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independently substituted aryl.In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independently substitutedheteroaryl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independentlyunsubstituted alkyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently unsubstituted heteroalkyl. In embodiments, R¹¹, R¹², R¹³,or R¹⁴ is independently unsubstituted cycloalkyl. In embodiments, R¹¹,R¹², R¹³, or R¹⁴ is independently unsubstituted heterocycloalkyl. Inembodiments, R¹¹, R¹², R¹³, or R¹⁴ is independently unsubstituted aryl.In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independently unsubstitutedheteroaryl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independentlysubstituted or unsubstituted C₁-C₄ alkyl. In embodiments, R¹¹, R¹², R¹³,or R¹⁴ is independently substituted or unsubstituted 2 to 4 memberedheteroalkyl.

In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independently substituted orunsubstituted C₃-C₆ cycloalkyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independentlysubstituted or unsubstituted phenyl. In embodiments, R¹¹, R¹², R¹³, orR¹⁴ is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independentlysubstituted C₁-C₄ alkyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently substituted 2 to 4 membered heteroalkyl. In embodiments,R¹¹, R¹², R¹³, or R¹⁴ is independently substituted C₃-C₆ cycloalkyl. Inembodiments, R¹¹, R¹², R¹³, or R¹⁴ is independently substituted 3 to 6membered heterocycloalkyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently substituted phenyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴is independently substituted 5 to 6 membered heteroaryl. In embodiments,R¹¹, R¹², R¹³, or R¹⁴ is independently unsubstituted C₁-C₄ alkyl. Inembodiments, R¹¹, R¹², R¹³, or R¹⁴ is independently unsubstituted 2 to 4membered heteroalkyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R¹¹, R¹²,R¹³, or R¹⁴ is independently unsubstituted 3 to 6 memberedheterocycloalkyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ is independentlyunsubstituted phenyl. In embodiments, R¹¹, R¹², R¹³, or R¹⁴ isindependently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R¹¹ and R¹² substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl. In embodiments, R¹¹ and R¹² substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heteroaryl. In embodiments, R¹¹ and R¹² substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted heterocycloalkyl. In embodiments, R¹¹ and R¹² substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted heteroaryl. In embodiments, R¹¹ and R¹² substituents bondedto the same nitrogen atom may optionally be joined to form anunsubstituted heterocycloalkyl. In embodiments, R¹¹ and R¹² substituentsbonded to the same nitrogen atom may optionally be joined to form anunsubstituted heteroaryl. In embodiments, R¹¹ and R¹² substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹¹ and R¹² substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R¹¹ and R¹² substituents bonded tothe same nitrogen atom may optionally be joined to form a substituted 3to 6 membered heterocycloalkyl. In embodiments, R¹¹ and R¹² substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted 5 to 6 membered heteroaryl. In embodiments, R¹¹ and R¹²substituents bonded to the same nitrogen atom may optionally be joinedto form an unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹¹ and R¹² substituents bonded to the same nitrogen atommay optionally be joined to form an unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently hydrogen, —CX^(C)₃, —CHX^(C) ₂, —CH₂X^(C), —CN, —COOH, —CONH₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently hydrogen. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently —CX^(C) ₃. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently —CHX^(C) ₂. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently —CH₂X^(C). In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently —CN. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently —COOH. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently —CONH₂. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently substituted or unsubstituted alkyl. In embodiments, R¹⁵,R¹⁶, R¹⁷, or R¹⁸ is independently substituted or unsubstitutedheteroalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independentlysubstituted or unsubstituted cycloalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷,or R¹⁸ is independently substituted or unsubstituted heterocycloalkyl.In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently substituted orunsubstituted aryl. In embodiments, R¹⁵, R¹⁶, R^(17,) or R¹⁸ isindependently substituted or unsubstituted heteroaryl. In embodiments,R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently substituted alkyl. Inembodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently substitutedheteroalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independentlysubstituted cycloalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently substituted heterocycloalkyl. In embodiments, R¹⁵, R¹⁶,R¹⁷, or R¹⁸ is independently substituted aryl. In embodiments, R¹⁵, R¹⁶,R¹⁷, or R¹⁸ is independently substituted heteroaryl. In embodiments,R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently unsubstituted alkyl. Inembodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently unsubstitutedheteroalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independentlyunsubstituted cycloalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently unsubstituted heterocycloalkyl. In embodiments, R¹⁵, R¹⁶,R¹⁷, or R¹⁸ is independently unsubstituted aryl. In embodiments, R¹⁵,R¹⁶, R¹⁷, or R¹⁸ is independently unsubstituted heteroaryl. Inembodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently substituted orunsubstituted C₁-C₄ alkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently substituted or unsubstituted 2 to 4 membered heteroalkyl.In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently substituted orunsubstituted C₃-C₆ cycloalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independentlysubstituted or unsubstituted phenyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, orR¹⁸ is independently substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independentlysubstituted C₁-C₄ alkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently substituted 2 to 4 membered heteroalkyl. In embodiments,R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently substituted C₃-C₆ cycloalkyl. Inembodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently substituted 3 to 6membered heterocycloalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently substituted phenyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸is independently substituted 5 to 6 membered heteroaryl. In embodiments,R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently unsubstituted C₁-C₄ alkyl. Inembodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independently unsubstituted 2 to 4membered heteroalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R¹⁵, R¹⁶,R¹⁷, or R¹⁸ is independently unsubstituted 3 to 6 memberedheterocycloalkyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ is independentlyunsubstituted phenyl. In embodiments, R¹⁵, R¹⁶, R¹⁷, or R¹⁸ isindependently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R¹⁵ and R¹⁶ substituents bonded to the same nitrogenatom may optionally be joined to form a substituted or unsubstitutedheterocycloalkyl. In embodiments, R¹⁵ and R¹⁶ substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heteroaryl. In embodiments, R¹⁵ and R¹⁶ substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted heterocycloalkyl. In embodiments, R¹⁵ and R¹⁶ substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted heteroaryl. In embodiments, R¹⁵ and R¹⁶ substituents bondedto the same nitrogen atom may optionally be joined to form anunsubstituted heterocycloalkyl. In embodiments, R¹⁵ and R¹⁶ substituentsbonded to the same nitrogen atom may optionally be joined to form anunsubstituted heteroaryl. In embodiments, R¹⁵ and R¹⁶ substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹⁵ and R¹⁶ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R¹⁵ and R¹⁶ substituents bonded tothe same nitrogen atom may optionally be joined to form a substituted 3to 6 membered heterocycloalkyl. In embodiments, R¹⁵ and R¹⁶ substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted 5 to 6 membered heteroaryl. In embodiments, R¹⁵ and R¹⁶substituents bonded to the same nitrogen atom may optionally be joinedto form an unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹⁵ and R¹⁶ substituents bonded to the same nitrogen atommay optionally be joined to form an unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, m1 is 1. In embodiments, m1 is 2. In embodiments, v1is 1. In embodiments, v1 is 2. In embodiments, m4 is 1. In embodiments,m4 is 2. In embodiments, m5 is 1. In embodiments, m5 is 2. Inembodiments, v4 is 1. In embodiments, v4 is 2. In embodiments, v5 is 1.In embodiments, v5 is 2. In embodiments, n1 is 0. In embodiments, n1is 1. In embodiments, n1 is 2. In embodiments, n1 is 3. In embodiments,n1 is 4. In embodiments, n4 is 0. In embodiments, n4 is 1. Inembodiments, n4 is 2. In embodiments, n4 is 3. In embodiments, n4 is 4.In embodiments, n5 is 0. In embodiments, n5 is 1. In embodiments, n5 is2. In embodiments, n5 is 3. In embodiments, n5 is 4.

In embodiments, X¹ is independently —Cl. In embodiments, X¹ isindependently —Br. In embodiments, X¹ is independently —I. Inembodiments, X¹ is independently —F. In embodiments, X² is independently—Cl. In embodiments, X² is independently —Br. In embodiments, X² isindependently —I. In embodiments, X² is independently —F. Inembodiments, X³ is independently —Cl. In embodiments, X³ isindependently —Br. In embodiments, X³ is independently —I. Inembodiments, X³ is independently —F. In embodiments, X⁴ is independently—Cl. In embodiments, X⁴ is independently —Br. In embodiments, X⁴ isindependently —I. In embodiments, X⁴ is independently —F. Inembodiments, X⁵ is independently —Cl. In embodiments, X⁵ isindependently —Br. In embodiments, X⁵ is independently —I. Inembodiments, X⁵ is independently —F. In embodiments, X^(A) isindependently —Cl. In embodiments, X^(A) is independently —Br. Inembodiments, X^(A) is independently —I. In embodiments, X^(A) isindependently —F. In embodiments, X^(B) is independently —Cl. Inembodiments, X^(B) is independently —Br. In embodiments, X^(B) isindependently —I. In embodiments, X^(B) is independently —F. Inembodiments, X^(C) is independently —Cl. In embodiments, X^(C) isindependently —Br. In embodiments, X^(C) is independently —I. Inembodiments, X^(C) is independently —F.

In embodiments, the compound has the formula:

R¹, R², R³, R⁴, R⁵, Ring A, Ring B, z1, z2, and z3 are as describedherein, including in compounds of formula (I) and (II). In embodiments,z1 is 0. In embodiments, z2 is 0. In embodiments, z3 is 0. Inembodiments, R² is hydrogen. In embodiments, R³ is hydrogen.

In embodiments, the compound has the formula:

R¹, R², R³, R⁴, R⁵, Ring A, Ring B, z1, z2, and z3 are as describedherein, including in compounds of formula (I) and (II).

In embodiments, the compound has the formula:

R¹, R², R³, R⁴, R⁵, Ring A, Ring B, z1, z2, and z3 are as describedherein, including in compounds of formula (I) and (II).

In embodiments, the compound has the formula:

R¹, R², R³, R⁴, R⁵, z1, z2, and z3 are as described herein, including incompounds of formula (I) to (V).

In embodiments, the compound has the formula:

R¹, R², R³, R⁴, R⁵, and z2 are as described herein, including incompounds of formula (I) to (V).

In embodiments, the compound has the formula:

R², R³, R⁴, R⁷, R⁸, R¹⁵, R¹⁶, and z2 are as described herein, includingin compounds of formula (I) to (V).

In embodiments, the compound has the formula:

R¹, R², R³, R⁴, z1, and z2 are as described herein, including incompounds of formula (I) to (V).

In embodiments, the compound has the formula:

R², R³, R⁴, and z2 are as described herein, including in compounds offormula (I) to (V).

In embodiments, the compound has the formula:

R², R³, and R⁴ are as described herein, including in compounds offormula (I) to (V).

In embodiments, the compound has the formula:

R⁴ is as described herein, including in compounds of formula (I) to (V).In embodiments, R⁴ is independently —OR¹⁴. In embodiments, R⁴ isindependently —SR¹⁴. In embodiments, 10⁴ is independently hydrogen orunsubstituted alkyl. In embodiments, R¹⁴ is independently hydrogen orunsubstituted C₁-C₆ alkyl. In embodiments, R¹⁴ is independently hydrogenor unsubstituted C₁-C₅ alkyl. In embodiments, R¹⁴ is independentlyhydrogen or unsubstituted C₁-C₄ alkyl. In embodiments, R¹⁴ isindependently hydrogen or unsubstituted C₁-C₃ alkyl. In embodiments, R¹⁴is independently hydrogen or unsubstituted C₁-C₂ alkyl. In embodiments,R¹⁴ is independently hydrogen or unsubstituted C₂-C₆ alkyl. Inembodiments, R¹⁴ is independently hydrogen or unsubstituted C₂-C₅ alkyl.In embodiments, R¹⁴ is independently hydrogen or unsubstituted C₂-C₄alkyl. In embodiments, R¹⁴ is independently hydrogen or unsubstitutedC₂-C₃ alkyl. In embodiments, R¹⁴ is independently hydrogen orunsubstituted C₃-C₆ alkyl. In embodiments, R¹⁴ is independently hydrogenor unsubstituted C₄-C₆ alkyl. In embodiments, R¹⁴ is independentlyhydrogen or unsubstituted C₅-C₆ alkyl. In embodiments, R¹⁴ isindependently hydrogen. In embodiments, R¹⁴ is independentlyunsubstituted alkyl. In embodiments, R¹⁴ is independently unsubstitutedC₁-C₆ alkyl. In embodiments, R¹⁴ is independently unsubstituted C₁-C₅alkyl. In embodiments, R¹⁴ is independently unsubstituted C₁-C₄ alkyl.In embodiments, R¹⁴ is independently unsubstituted C₁-C₃ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₁-C₂ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₅ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₄ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₃ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₃-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₄-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₅-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted methyl. In embodiments,R¹⁴ is independently unsubstituted ethyl. In embodiments, R¹⁴ isindependently unsubstituted propyl. In embodiments, R¹⁴ is independentlyunsubstituted isopropyl. In embodiments, R¹⁴ is independentlyunsubstituted tert-butyl.

In embodiments, the compound has the formula:

R⁴ is as described herein, including in compounds of formula (I) to (V).In embodiments, R⁴ is independently —OR¹⁴. In embodiments, R⁴ isindependently —SR¹⁴. In embodiments, R¹⁴ is independently hydrogen orunsubstituted alkyl. In embodiments, R¹⁴ is independently hydrogen orunsubstituted C₁-C₆ alkyl. In embodiments, R¹⁴ is independently hydrogenor unsubstituted C₁-C₅ alkyl. In embodiments, R¹⁴ is independentlyhydrogen or unsubstituted C₁-C₄ alkyl. In embodiments, R¹⁴ isindependently hydrogen or unsubstituted C₁-C₃ alkyl. In embodiments, R¹⁴is independently hydrogen or unsubstituted C₁-C₂ alkyl. In embodiments,R¹⁴ is independently hydrogen or unsubstituted C₂-C₆ alkyl. Inembodiments, R¹⁴ is independently hydrogen or unsubstituted C₂-C₅ alkyl.In embodiments, R¹⁴ is independently hydrogen or unsubstituted C₂-C₄alkyl. In embodiments, R¹⁴ is independently hydrogen or unsubstitutedC₂-C₃ alkyl. In embodiments, R¹⁴ is independently hydrogen orunsubstituted C₃-C₆ alkyl. In embodiments, R¹⁴ is independently hydrogenor unsubstituted C₄-C₆ alkyl. In embodiments, R¹⁴ is independentlyhydrogen or unsubstituted C₅-C₆ alkyl. In embodiments, R¹⁴ isindependently hydrogen. In embodiments, R¹⁴ is independentlyunsubstituted alkyl. In embodiments, R¹⁴ is independently unsubstitutedC₁-C₆ alkyl. In embodiments, R¹⁴ is independently unsubstituted C₁-C₅alkyl. In embodiments, R¹⁴ is independently unsubstituted C₁-C₄ alkyl.In embodiments, R¹⁴ is independently unsubstituted C₁-C₃ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₁-C₂ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₅ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₄ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₃ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₃-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₄-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₅-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted methyl. In embodiments,R¹⁴ is independently unsubstituted ethyl. In embodiments, R¹⁴ isindependently unsubstituted propyl. In embodiments, R¹⁴ is independentlyunsubstituted isopropyl. In embodiments, R¹⁴ is independentlyunsubstituted tert-butyl.

In embodiments, the compound has the formula:

R⁴ is as described herein, including in compounds of formula (I) to (V).In embodiments, R⁴ is independently —OR¹⁴. In embodiments, R⁴ isindependently —SR¹⁴. In embodiments, R¹⁴ is independently hydrogen orunsubstituted alkyl. In embodiments, R¹⁴ is independently hydrogen orunsubstituted C₁-C₆ alkyl. In embodiments, R¹⁴ is independently hydrogenor unsubstituted C₁-C₅ alkyl. In embodiments, R¹⁴ is independentlyhydrogen or unsubstituted C₁-C₄ alkyl. In embodiments, R¹⁴ isindependently hydrogen or unsubstituted C₁-C₃ alkyl. In embodiments, R⁴is independently hydrogen or unsubstituted C₁-C₂ alkyl. In embodiments,R¹⁴ is independently hydrogen or unsubstituted C₂-C₆ alkyl. Inembodiments, R¹⁴ is independently hydrogen or unsubstituted C₂-C₅ alkyl.In embodiments, R¹⁴ is independently hydrogen or unsubstituted C₂-C₄alkyl. In embodiments, R¹⁴ is independently hydrogen or unsubstitutedC₂-C₃ alkyl. In embodiments, R¹⁴ is independently hydrogen orunsubstituted C₃-C₆ alkyl. In embodiments, R⁴ is independently hydrogenor unsubstituted C₄-C₆ alkyl. In embodiments, R¹⁴ is independentlyhydrogen or unsubstituted C₅-C₆ alkyl. In embodiments, R¹⁴ isindependently hydrogen. In embodiments, R¹⁴ is independentlyunsubstituted alkyl. In embodiments, R¹⁴ is independently unsubstitutedC₁-C₆ alkyl. In embodiments, R¹⁴ is independently unsubstituted C₁-C₅alkyl. In embodiments, R¹⁴ is independently unsubstituted C₁-C₄ alkyl.In embodiments, R¹⁴ is independently unsubstituted C₁-C₃ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₁-C₂ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₅ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₄ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₂-C₃ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₃-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₄-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted C₅-C₆ alkyl. Inembodiments, R¹⁴ is independently unsubstituted methyl. In embodiments,R⁴ is independently unsubstituted ethyl. In embodiments, R¹⁴ isindependently unsubstituted propyl. In embodiments, R¹⁴ is independentlyunsubstituted isopropyl. In embodiments, R¹⁴ is independentlyunsubstituted tert-butyl.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, R¹ is independently hydrogen, oxo, halogen, —CX¹ ₃,—CHX¹ ₂, —OCH₂X¹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹ ₃, —OCHX'₂, —OCH₂X¹, R³⁰-substitutedor unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁰-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 memberedheteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),R³⁰-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl,C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁰-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁰-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R³⁰-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X¹ is halogen. Inembodiments, X¹ is F. In embodiments, R¹ is independently halogen, —CX¹₃, —CHX'₂, —OCH₂X¹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO4H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹ ₃, —OCHX'₂, —OCH₂X¹, R³⁰-substitutedor unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁰-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 memberedheteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),R³⁰-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl,C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁰-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁰-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R³⁰-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R³⁰ is independently oxo, halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —CH₂X³⁰, —OCH₂X³⁰,—OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX³⁰ ₃, R³¹-substituted or unsubstituted alkyl(e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³¹-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R³¹-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R³¹-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³¹-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R³¹-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X³⁰ is halogen. Inembodiments, X³⁰ is F.

R³¹ is independently oxo, halogen, —CX³¹ ₃, —CHX³¹ ₂, —CH₂X³¹, —OCH₂X³¹,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX³¹ ₃, —OCHX³¹ ₂, R³²-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³²-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R³²-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R³²-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³²-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R³²-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X³¹ is halogen. Inembodiments, X³¹ is F.

In embodiments, R² is independently hydrogen, oxo, halogen, —CX² ₃,—CHX² ₂, —CH₂X², —OCH₂X², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX² ₃, —OCHX² ₂,R³³-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R³³-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³³-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³³-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³³-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X² is halogen. In embodiments, X² is F.

In embodiments, R² is independently halogen, —CX² ₃, —CHX² ₂, —OCH₂X²,—CH₂X², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX² ₃, —OCHX² ₂, R³³-substituted or unsubstitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³³-substitutedor unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R³³-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R³³-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³³-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R³³-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R²is hydrogen.

R³³ is independently oxo, halogen, —CX³³ ₃, —CHX³³ ₂, —CHX³³ ₂,—OCH₂X³³, —OCHX³³ ₂, —CN, —OH, —NH₂, —COON, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³³ ₃, —OCHX³³ ₂, R³⁴-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R³⁴-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 memberedheteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),R³⁴-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl,C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁴-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁴-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R³⁴-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X³³ is halogen. Inembodiments, X³³ is F.

R³⁴ is independently oxo, halogen, —CX³⁴ ₃, —CHX³⁴ ₂, —CH₂X³⁴ ₂,—OCH₂X³⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX³⁴ ₃, —OCHX³⁴ ₂, R³⁵-substituted or unsubstitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁵-substitutedor unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R³⁵-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R³⁵-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁵-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R³⁵-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X³⁴ is halogen. Inembodiments, X³⁴ is F.

In embodiments, R³ is independently hydrogen, oxo, halogen, —CX³ ₃,—CHX³ ₂, —CH₂X³, —OCH₂X³, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³ ₃, —OCHX³ ₂,R³⁶-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R³⁶-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁶-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁶-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X³ is halogen. In embodiments, X³ is F. In embodiments, R³ isindependently halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —OCH₂X³, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³₃, —OCHX³ ₂, R³⁶-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁶-substituted or unsubstitutedheteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 memberedheteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl,or 2 to 4 membered heteroalkyl), R³⁶-substituted or unsubstitutedcycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆cycloalkyl), R³⁶-substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), R³⁶-substituted or unsubstituted aryl(e.g. C₆-C₁₀ aryl or C₆ aryl), or R³⁶-substituted or unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R³ ishydrogen.

R³⁶ is independently oxo, halogen, —CX³⁶ ₃, —CHX³⁶ ₂, —CH₂X³⁶, —OCH₂X³⁶,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX³⁶ ₃, —OCHX³⁶ ₂, R³⁷-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁷-substituted or unsubstitutedheteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 memberedheteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl,or 2 to 4 membered heteroalkyl), R³⁷-substituted or unsubstitutedcycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆cycloalkyl), R³⁷-substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), R³⁷-substituted or unsubstituted aryl(e.g. C₆-C₁₀ aryl or C₆ aryl), or R³⁷-substituted or unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). X³⁶ is halogen. Inembodiments, X³⁶ is F.

R³⁷ is independently oxo, halogen, —CX³⁷ ₃, —CHX³⁷ ₂, —CH₂X³⁷, —OCH₂X³⁷,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX³⁷ ₃, —OCHX³⁷ ₂, R³⁸-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R³⁸-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R³⁸-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R³⁸-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R³⁸-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R³⁸-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X³⁷ is halogen. Inembodiments, X³⁷ is F.

In embodiments, R⁴ is independently hydrogen, oxo, halogen, —CX⁴ ₃,—CHX⁴ ₂, —CH₂X⁴, —OCH₂X⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴ ₃, —OCHX⁴ ₂,R³⁹-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R³⁹-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R³⁹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R³⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R³⁹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR³⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X⁴ is halogen. In embodiments, X⁴ is F. In embodiments, R⁴ isindependently halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —OCH₂X⁴, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴₃, —OCHX⁴ ₂, R³⁹-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl,C₁-C₆ alkyl, or C₁-C₄ alkyl), R″-substituted or unsubstitutedheteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 memberedheteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl,or 2 to 4 membered heteroalkyl), R³⁹-substituted or unsubstitutedcycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆cycloalkyl), R³⁹-substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), R³⁹-substituted or unsubstituted aryl(e.g. C₆-C₁₀ aryl or C₆ aryl), or R³⁹-substituted or unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

R³⁹ is independently oxo, halogen, —CX³⁹ ₃, —CHX³⁹ ₂, —CH₂X³⁹, —OCH₂X³⁹,—OCHX³⁹ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX³⁹ ₃, —OCHX³⁹ ₂, R⁴⁰-substituted or unsubstitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁰-substitutedor unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁰-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁴⁰-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁰-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁴⁰-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X³⁹ is halogen. Inembodiments, X³⁹ is F.

R⁴⁰ is independently oxo, halogen, —CX⁴⁰ ₃, —CHX⁴⁰ ₂, —CH₂X⁴⁰, —OCH₂X⁴⁰,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁴⁰ ₃, —OCHX⁴⁰ ₂, R⁴¹-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴¹-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁴¹-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁴¹-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴¹-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁴¹-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁴⁰ is halogen. Inembodiments, X⁴⁰ is F.

In embodiments, R⁵ is independently hydrogen, oxo, halogen, —CX⁵ ₃,—CHX⁵ ₂, —CH₂X⁵, —OCH₂X⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵ ₃, —OCHX⁵ ₂,R⁴²-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁴²-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴²-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴²-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴²-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X⁵ is halogen. In embodiments, X⁵ is F.

In embodiments, R⁵ is independently halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵,—OCH₂X⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX⁵ ₃, —OCHX⁵ ₂, R⁴²-substituted or unsubstitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴²-substitutedor unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁴²-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁴²-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴²-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁴²-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl).

R⁴² is independently oxo, halogen, —CX⁴² ₃, —CHX⁴² ₂, —CH₂X⁴², —OCH₂X⁴²,—OCHX⁴² ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX⁴² ₃, —OCHX⁴² ₂, R⁴³-substituted or unsubstitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴³-substitutedor unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁴³-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁴³-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴³-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁴³-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁴² is halogen. Inembodiments, X⁴² is F.

R⁴³ is independently oxo, halogen, —CX⁴³ ₃, —CHX⁴³ ₂, —CH₂X⁴³, —OCH₂X⁴³,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁴³ ₃, —OCHX⁴³ ₂, R⁴⁴-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁴-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁴-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁴⁴-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁴-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁴⁴-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁴³ is halogen. Inembodiments, X⁴³ is F.

In embodiments, R⁷ is independently hydrogen, oxo, halogen, —CX⁷ ₃,—CHX⁷ ₂, —CH₂X⁷, —OCH₂X⁷, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁷ ₃, —OCHX⁷ ₂,R⁴⁸-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁴⁸-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁴⁸-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁴⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁴⁸-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁴⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X⁷ is halogen. In embodiments, X⁷ is F. In embodiments, R⁷ and R⁸substituents bonded to the same nitrogen atom may optionally be joinedto form a R⁴⁸-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl), or R⁴⁸-substituted or unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁷ is independently hydrogen or unsubstituted alkyl. Inembodiments, R⁷ is independently hydrogen or unsubstituted C₁-C₆ alkyl.In embodiments, R⁷ is independently hydrogen or unsubstituted C₁-C₅alkyl. In embodiments, R⁷ is independently hydrogen or unsubstitutedC₁-C₄ alkyl. In embodiments, R⁷ is independently hydrogen orunsubstituted C₁-C₃ alkyl. In embodiments, R⁷ is independently hydrogenor unsubstituted C₁-C₂ alkyl. In embodiments, R⁷ is independentlyhydrogen or unsubstituted C₂-C₆ alkyl. In embodiments, R⁷ isindependently hydrogen or unsubstituted C₂-C₅ alkyl. In embodiments, R⁷is independently hydrogen or unsubstituted C₂-C₄ alkyl. In embodiments,R⁷ is independently hydrogen or unsubstituted C₂-C₃ alkyl. Inembodiments, R⁷ is independently hydrogen or unsubstituted C₃-C₆ alkyl.In embodiments, R⁷ is independently hydrogen or unsubstituted C₄-C₆alkyl. In embodiments, R⁷ is independently hydrogen or unsubstitutedC₅-C₆ alkyl. In embodiments, R⁷ is independently hydrogen. Inembodiments, R⁷ is independently unsubstituted alkyl. In embodiments, R⁷is independently unsubstituted C₁-C₆ alkyl. In embodiments, R⁷ isindependently unsubstituted C₁-C₅ alkyl. In embodiments, R⁷ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁷ isindependently unsubstituted C₁-C₃ alkyl. In embodiments, R⁷ isindependently unsubstituted C₁-C₂ alkyl. In embodiments, R⁷ isindependently unsubstituted C₂-C₆ alkyl. In embodiments, R⁷ isindependently unsubstituted C₂-C₅ alkyl. In embodiments, R⁷ isindependently unsubstituted C₂-C₄ alkyl. In embodiments, R⁷ isindependently unsubstituted C₂-C₃ alkyl. In embodiments, R⁷ isindependently unsubstituted C₃-C₆ alkyl. In embodiments, R⁷ isindependently unsubstituted C₄-C₆ alkyl. In embodiments, R⁷ isindependently unsubstituted C₅-C₆ alkyl. In embodiments, R⁷ is hydrogen.In embodiments, R⁷ is independently hydrogen, halogen, —CX⁷ ₃, CHX⁷ ₂,CH₂X⁷, —CN, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁷and R⁸ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl.

R⁴⁸ is independently oxo, halogen, —CX⁴⁸ ₃, —CHX⁴⁸ ₂, —CH₂X⁴⁸, —OCH₂X⁴⁸,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁴⁸ ₃, —OCHX⁴⁸ ₂, R⁴⁹-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁴⁹-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁴⁹-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁴⁹-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁴⁹-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁴⁹-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁴⁸ is halogen. Inembodiments, X⁴⁸ is F.

R⁴⁹ is independently oxo, halogen, —CX⁴⁹ ₃, —CHX⁴⁹ ₂, —CH₂X⁴⁹, —OCH₂X⁴⁹,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁴⁹ ₃, —OCHX⁴⁹ ₂, R⁵⁰-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵⁰-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁵⁰-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁵⁰-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵⁰-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁵⁰-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁴⁹ is halogen. Inembodiments, X⁴⁹ is F.

In embodiments, R⁸ is independently hydrogen, oxo, halogen, —CX⁸ ₃,—CHX⁸ ₂, —CH₂X⁸, —OCH₂X⁸, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, NHNH₂, ON I₂, NHC═(O)NHNH₂, NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCHX⁸ ₂, R⁵¹-substituted or unsubstitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵¹-substitutedor unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁵¹-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁵¹-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵¹-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁵¹-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁸ is halogen. Inembodiments, X⁸ is F. In embodiments, X⁷ is F. In embodiments, R⁷ and R⁸substituents bonded to the same nitrogen atom may optionally be joinedto form a R⁵¹-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R⁵¹-substituted or unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl).

In embodiments, R⁸ is independently hydrogen or unsubstituted alkyl. Inembodiments, R⁸ is independently hydrogen or unsubstituted C₁-C₆ alkyl.In embodiments, R⁸ is independently hydrogen or unsubstituted C₁-C₅alkyl. In embodiments, R⁸ is independently hydrogen or unsubstitutedC₁-C₄ alkyl. In embodiments, R⁸ is independently hydrogen orunsubstituted C₁-C₃ alkyl. In embodiments, R⁸ is independently hydrogenor unsubstituted C₁-C₂ alkyl. In embodiments, R⁸ is independentlyhydrogen or unsubstituted C₂-C₆ alkyl. In embodiments, R⁸ isindependently hydrogen or unsubstituted C₂-C₅ alkyl. In embodiments, R⁸is independently hydrogen or unsubstituted C₂-C₄ alkyl. In embodiments,R⁸ is independently hydrogen or unsubstituted C₂-C₃ alkyl. Inembodiments, R⁸ is independently hydrogen or unsubstituted C₃-C₆ alkyl.In embodiments, R⁸ is independently hydrogen or unsubstituted C₄-C₆alkyl. In embodiments, R⁸ is independently hydrogen or unsubstitutedC₅-C₆ alkyl. In embodiments, R⁸ is independently hydrogen. Inembodiments, R⁸ is independently unsubstituted alkyl. In embodiments, R⁸is independently unsubstituted C₁-C₆ alkyl. In embodiments, R⁸ isindependently unsubstituted C₁-C₅ alkyl. In embodiments, R⁸ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁸ isindependently unsubstituted C₁-C₃ alkyl. In embodiments, R⁸ isindependently unsubstituted C₁-C₂ alkyl. In embodiments, R⁸ isindependently unsubstituted C₂-C₆ alkyl. In embodiments, R⁸ isindependently unsubstituted C₂-C₅ alkyl. In embodiments, R⁸ isindependently unsubstituted C₂-C₄ alkyl. In embodiments, R⁸ isindependently unsubstituted C₂-C₃ alkyl. In embodiments, R⁸ isindependently unsubstituted C₃-C₆ alkyl. In embodiments, R⁸ isindependently unsubstituted C₄-C₆ alkyl. In embodiments, R⁸ isindependently unsubstituted C₅-C₆ alkyl. In embodiments, R⁸ is hydrogen.In embodiments, R⁸ is independently hydrogen, halogen, —CX⁸ ₃, —CHX⁸ ₂,—CH₂X⁸, —CN, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R⁵¹ is independently oxo, halogen, —CX⁵¹ ₃, —CHX⁵¹ ₂, —CH₂X⁵¹, —OCH₂X⁵¹,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁵¹ ₃, —OCHX⁵¹ ₂, R⁵²-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵²-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁵²-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁵²-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵²-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁵²-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁵¹ is halogen. Inembodiments, X⁵¹ is F.

R⁵² is independently oxo, halogen, —CX⁵² ₃, —CHX⁵² ₂, —CH₂X⁵², —OCH₂X⁵²,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁵² ₃, —OCHX⁵² ₂, R⁵³-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵³-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁵³-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁵³-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵³-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁵³-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁵² is halogen. Inembodiments, X⁵² is F.

In embodiments, R⁹ is independently hydrogen, oxo, halogen, —CX⁹ ₃,—CHX⁹ ₂, —CH₂X⁹, —OCH₂X⁹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹ ₃, —OCHX⁹ ₂,R⁵⁴-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁵⁴-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁴-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁴-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁴-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵⁴-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X⁹ is halogen. In embodiments, X⁹ is F. In embodiments, R⁹ is hydrogen.In embodiments, R⁹ is independently hydrogen, halogen, —CX⁹ ₃, —CHX⁹ ₂,—CH₂X⁹, —CN, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R⁵⁴ is independently oxo, halogen, —CX⁵⁴ ₃, —CHX⁵⁴ ₂, —CH₂X⁵⁴, —OCH₂X⁵⁴,—OCHX⁵⁴ ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX⁵⁴ ₃, —OCHX⁵⁴ ₂, R⁵⁵-substituted or unsubstitutedalkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵⁵-substitutedor unsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁵⁵-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁵⁵-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵⁵-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁵⁵-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁵⁴ is halogen. Inembodiments, X⁵⁴ is F.

R⁵⁵ is independently oxo, halogen, —CX⁵⁵ ₃, —CHX⁵⁵ ₂, —CH₂X⁵⁵, —OCH₂X⁵⁵,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, NHNH₂,ONH₂, NHC═(O)NHNH₂, NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁵⁵ ₃, —OCHX⁵⁵ ₂, R⁵⁶-substituted or unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵⁶-substituted or unsubstitutedheteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8 memberedheteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl,or 2 to 4 membered heteroalkyl), R⁵⁶-substituted or unsubstitutedcycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆cycloalkyl), R⁵⁶-substituted or unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), R⁵⁶-substituted or unsubstituted aryl(e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁵⁶-substituted or unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). X⁵⁵ is halogen. Inembodiments, X⁵⁵ is F.

In embodiments, R¹⁰ is independently hydrogen, oxo, halogen, —CX¹⁰ ₃,—CHX¹⁰ ₂, —CH₂X¹⁰, —OCH₂X¹⁰, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹⁰ ₃, —OCHX¹⁰ ₂,R⁵⁷-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁵⁷-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁵⁷-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁵⁷-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁵⁷-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁵⁷-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X¹⁰ is halogen. In embodiments, X¹⁰ is F. In embodiments, R¹⁰ ishydrogen. In embodiments, R¹⁰, is independently hydrogen, halogen, —CX¹⁰₃, —CHX¹⁰ ₂, —CH₂X¹⁰, —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁵⁷ is independently oxo, halogen, —CX⁵⁷ ₃, —CHX⁵⁷ ₂, —CH₂X⁵⁷, —OCH₂X⁵⁷,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁵⁷ ₃, —OCHX⁵⁷ ₂, R⁵⁸-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵⁸-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁵⁸-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁵⁸-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵⁸-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁵⁸-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁵⁷ is halogen. Inembodiments, X⁵⁷ is F.

R⁵⁸ is independently oxo, halogen, —CX⁵⁸ ₃, —CHX⁵⁸ ₂, —CH₂X⁵⁸, —OCH₂X⁵⁸,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁵⁸ ₃, —OCHX⁵⁸ ₂, R⁵⁹-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁵⁹-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁵⁹-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁵⁹-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁵⁹-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁵⁹-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁵⁸ is halogen. Inembodiments, X⁵⁸ is F.

In embodiments, R¹¹ is independently hydrogen, oxo, halogen, —CHX¹¹ ₂,—CH₂X¹¹, —OCH₂X¹¹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹¹ ₃, —OCHX¹¹ ₂, R⁶⁰-substituted orunsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),R⁶⁰-substituted or unsubstituted heteroalkyl (e.g. 2 to 10 memberedheteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 membered heteroalkyl, 2to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl),R⁶⁰-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl,C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶⁰-substituted or unsubstitutedheterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁶⁰-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁶⁰-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X¹¹ is halogen. Inembodiments, X¹¹ is F. In embodiments, R¹¹ and R¹² substituents bondedto the same nitrogen atom may optionally be joined to form aR⁶⁰-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8 memberedheterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6 memberedheterocycloalkyl) or R⁶⁰-substituted or unsubstituted heteroaryl (e.g. 5to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6membered heteroaryl). In embodiments, R¹⁴ is hydrogen. In embodiments,R¹⁴ is independently hydrogen, halogen, —CX¹¹ ₃, —CHX¹¹ ₂, CH₂X¹¹, —CN,—COOH, —CONH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

R⁶⁰ is independently oxo, halogen, —CX⁶⁰ ₃, —CHX⁶⁰ ₂, —CH₂X⁶⁰, —OCH₂X⁶⁰,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁶⁰ ₃, —OCHX⁶⁰ ₂, R⁶¹-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁶¹-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁶¹-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁶¹-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁶¹-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁶¹-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁶⁰ is halogen. Inembodiments, X⁶⁰ is F.

R⁶¹ is independently oxo, halogen, —CX⁶¹ ₃, —CHX⁶¹ ₂, —CH₂X⁶¹, —OCH₂X⁶¹,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁶¹ ₃, —OCHX⁶¹ ₂, R⁶²-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁶²-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁶²-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁶²-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁶²-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁶²-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁶¹ is halogen. Inembodiments, X⁶¹ is F.

In embodiments, R¹² is independently hydrogen, oxo, halogen, —CX¹² ₃,—CHX¹² ₂, —CH₂X¹², —OCH₂X¹², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹² ₃, —OCHX¹² ₂,R⁶³-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁶³-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶³-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶³-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶³-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶³-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X¹² is halogen. In embodiments, X¹² is F. In embodiments, R¹¹ and R¹²substituents bonded to the same nitrogen atom may optionally be joinedto form a R⁶³-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R⁶³-substituted or unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹² ishydrogen. In embodiments, R¹² is independently hydrogen, halogen, —CX¹²₃, —CHH¹² ₂, —CH₂X¹², —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁶³ is independently oxo, halogen, —CX⁶³ ₃, —CHX⁶³ ₂, —CH₂X⁶³, —OCH₂X⁶³,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁶³ ₃, —OCHX⁶³ ₂, R⁶⁴-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁶⁴-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁶⁴-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁶⁴-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁶⁴-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁶⁴-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁶³ is halogen. Inembodiments, X⁶³ is F.

R⁶⁴ is independently oxo, halogen, —CX⁶⁴ ₃, —CHX⁶⁴ ₂, —CH₂X⁶⁴, —OCH₂X⁶⁴,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁶⁴ ₃, —OCHX⁶⁴ ₂, R⁶⁵-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁶⁵-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁶⁵-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁶⁵-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁶⁵-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁶⁵-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁶⁴ is halogen. Inembodiments, X⁶⁴ is F.

In embodiments, R¹³ is independently hydrogen, oxo, halogen, —CX¹³ ₃,—CHX¹³ ₂, —CH₂X¹³, —OCH₂X¹³, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹³ ₃, —OCHX¹³ ₂,R⁶⁶-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁶⁶-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶⁶-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶⁶-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶⁶-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶⁶-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X¹³ is halogen. In embodiments, X¹³ is F. In embodiments, R¹³ ishydrogen. In embodiments, R¹³ is independently hydrogen, halogen, —CX¹³₃, —CHX¹³ ₂, —CH₂X¹³, —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁶⁶ is independently oxo, halogen, —CX⁶⁶ ₃, —CHX⁶⁶ ₂, —CH₂X⁶⁶, —OCH₂X⁶⁶,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁶⁶ ₃, —OCHX⁶⁶ ₂, R⁶⁷-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁶⁷-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁶⁷-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁶⁷-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁶⁷-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁶⁷-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁶⁶ is halogen. Inembodiments, X⁶⁶ is F.

R⁶⁷ is independently oxo, halogen, —CX⁶⁷ ₃, —CHX⁶⁷ ₂, —CH₂X⁶⁷, —OCH₂X⁶⁷,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁶⁷ ₃, —OCHX⁶⁷ ₂, R⁶⁸-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁶⁸-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁶⁸-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁶⁸-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁶⁸-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁶⁸-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁶⁷ is halogen. Inembodiments, X⁶⁷ is F.

In embodiments, R¹⁴ is independently hydrogen, oxo, halogen, —CX¹⁴ ₃,—CHX¹⁴ ₂, —CH₂X¹⁴, —OCH₂X¹⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹⁴ ₃, —OCHX14₂,R⁶⁹-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁶⁹-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁶⁹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁶⁹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁶⁹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁶⁹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X¹⁴ is halogen. In embodiments, X¹⁴ is F. In embodiments, R¹⁴ ishydrogen. In embodiments, R¹⁴ is independently hydrogen, halogen, —CX¹⁴₃, CHX¹⁴ ₂, —CH₂X¹⁴, —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁶⁹ is independently oxo, halogen, —CX⁶⁹ ₃, —CHX⁶⁹ ₂, —CH₂X⁶⁹, —OCH₂X⁶⁹,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁶⁹ ₃, —OCHX⁶⁹ ₂, R⁷⁰-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁷⁰-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁷⁰-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁷⁰-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁷⁰-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁷⁰-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁶⁹ is halogen. Inembodiments, X⁶⁹ is F.

R⁷⁰ is independently oxo, halogen, —CX⁷⁰ ₃, —CHX⁷⁰ ₂, —CH₂X⁷⁰, —OCH₂X⁷⁰,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁷⁰ ₃, —OCHX⁷⁰ ₂, R⁷¹-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁷¹-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁷¹-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁷¹-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁷¹-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁷¹-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁷⁰ is halogen. Inembodiments, X⁷⁰ is F.

In embodiments, ^(R′5) is independently hydrogen, oxo, halogen, —CX¹⁵ ₃,—CHX¹⁵ ₂, —CH₂X¹⁵, —OCH₂X¹⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ON¹⁴ ₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹⁵ ₃, —OCHX¹⁵ ₂,R⁷²-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁷²-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷²-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷²-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷²-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷²-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X¹⁵ is halogen. In embodiments, X¹⁵ is F. In embodiments, R¹⁵ and R¹⁶substituents bonded to the same nitrogen atom may optionally be joinedto form a R⁷²-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R⁷²-substituted or unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, 10⁵ ishydrogen. In embodiments, R¹⁵ is independently hydrogen, halogen, —CX¹⁵₃, CHX¹⁵ ₂, CH₂X¹⁵, —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R¹⁵ is independently hydrogen or unsubstituted alkyl. Inembodiments, R¹⁵ is independently hydrogen or unsubstituted C₁-C₆ alkyl.In embodiments, R¹⁵ is independently hydrogen or unsubstituted C₁-C₅alkyl. In embodiments, R¹⁵ is independently hydrogen or unsubstitutedC₁-C₄ alkyl. In embodiments, R¹⁵ is independently hydrogen orunsubstituted C₁-C₃ alkyl. In embodiments, R¹⁵ is independently hydrogenor unsubstituted C₁-C₂ alkyl. In embodiments, R¹⁵ is independentlyhydrogen or unsubstituted C₂-C₆ alkyl. In embodiments, R¹⁵ isindependently hydrogen or unsubstituted C₂-C₅ alkyl. In embodiments, R¹⁵is independently hydrogen or unsubstituted C₂-C₄ alkyl. In embodiments,R¹⁵ is independently hydrogen or unsubstituted C₂-C₃ alkyl. Inembodiments, R¹⁵ is independently hydrogen or unsubstituted C₃-C₆ alkyl.In embodiments, R¹⁵ is independently hydrogen or unsubstituted C₄-C₆alkyl. In embodiments, R¹⁵ is independently hydrogen or unsubstitutedC₅-C₆ alkyl. In embodiments, R¹⁵ is independently hydrogen. Inembodiments, R¹⁵ is independently unsubstituted alkyl. In embodiments,R¹⁵ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₁-C₅ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₁-C₃ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₁-C₂ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₂-C₆ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₂-C₅ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₂-C₄ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₂-C₃ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₃-C₆ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₄-C₆ alkyl. In embodiments, R¹⁵ isindependently unsubstituted C₅-C₆ alkyl.

R⁷² is independently oxo, halogen, —CX⁷² ₃, —CHX⁷² ₂, —CH₂X⁷², —OCH₂X⁷²,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁷² ₃, —OCHX⁷² ₂, R⁷³-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁷³-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁷³-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁷³-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁷³-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁷³-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁷² is halogen. Inembodiments, X⁷² is F.

R⁷³ is independently oxo, halogen, —CX⁷³ ₃, —CHX⁷³ ₂, —CH₂X⁷³, —OCH₂X⁷³,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁷³ ₃, —OCHX⁷³ ₂, R⁷⁴-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁷⁴-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁷⁴-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁷⁴-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁷⁴-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁷⁴-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁷³ is halogen. Inembodiments, X⁷³ is F.

In embodiments, R¹⁶ is independently hydrogen, oxo, halogen, —CX¹⁶ ₃,—CHX¹⁶ ₂, —CH₂X¹⁶, —OCH₂X¹⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹⁶ ₃, —OCHX¹⁶ ₂,R⁷⁵-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁷⁵-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷⁵-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷⁵-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷⁵-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷⁵-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X¹⁶ is halogen. In embodiments, X¹⁶ is F. In embodiments, R¹⁵ and R¹⁶substituents bonded to the same nitrogen atom may optionally be joinedto form a R⁷⁵-substituted or unsubstituted heterocycloalkyl (e.g. 3 to 8membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5 to 6membered heterocycloalkyl) or R⁷⁵-substituted or unsubstitutedheteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9 memberedheteroaryl, or 5 to 6 membered heteroaryl). In embodiments, R¹⁶ ishydrogen. In embodiments, R¹⁶ is independently hydrogen, halogen, —CX¹⁶₃, —CHX¹⁶ ₂, CH₂X¹⁶, —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In embodiments, R¹⁶ is independently hydrogen or unsubstituted alkyl. Inembodiments, R¹⁶ is independently hydrogen or unsubstituted C₁-C₆ alkyl.In embodiments, R¹⁶ is independently hydrogen or unsubstituted C₁-C₅alkyl. In embodiments, R¹⁶ is independently hydrogen or unsubstitutedC₁-C₄ alkyl. In embodiments, R¹⁶ is independently hydrogen orunsubstituted C₁-C₃ alkyl. In embodiments, R¹⁶ is independently hydrogenor unsubstituted C₁-C₂ alkyl. In embodiments, R¹⁶ is independentlyhydrogen or unsubstituted C₂-C₆ alkyl. In embodiments, R¹⁶ isindependently hydrogen or unsubstituted C₂-C₅ alkyl. In embodiments, R¹⁶is independently hydrogen or unsubstituted C₂-C₄ alkyl. In embodiments,R¹⁶ is independently hydrogen or unsubstituted C₂-C₃ alkyl. Inembodiments, R¹⁶ is independently hydrogen or unsubstituted C₃-C₆ alkyl.In embodiments, R¹⁶ is independently hydrogen or unsubstituted C₄-C₆alkyl. In embodiments, R¹⁶ is independently hydrogen or unsubstitutedC₅-C₆ alkyl. In embodiments, R¹⁶ is independently hydrogen. Inembodiments, R¹⁶ is independently unsubstituted alkyl. In embodiments,R¹⁶ is independently unsubstituted C₁-C₆ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₁-C₅ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₁-C₃ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₁-C₂ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₂-C₆ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₂-C₅ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₂-C₄ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₂-C₃ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₃-C₆ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₄-C₆ alkyl. In embodiments, R¹⁶ isindependently unsubstituted C₅-C₆ alkyl.

R⁷⁵ is independently oxo, halogen, —CX⁷⁵ ₃, —CHX⁷⁵ ₂, —CH₂X⁷⁵, —OCH₂X⁷⁵,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁷⁵ ₃, —OCHX⁷⁵ ₂, R⁷⁶-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁷⁶-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁷⁶-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁷⁶-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁷⁶-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁷⁶-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁷⁵ is halogen. Inembodiments, X⁷⁵ is F.

R⁷⁶ is independently oxo, halogen, —CX⁷⁶ ₃, —CHX⁷⁶ ₂, —CH₂X⁷⁶, —OCH₂X⁷⁶,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁷⁶ ₃, —OCHX⁷⁶ ₂, R⁷⁷-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁷⁷-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁷⁷-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁷⁷-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁷⁷-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁷⁷-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁷⁶ is halogen. Inembodiments, X⁷⁶ is F.

In embodiments, R¹⁷ is independently hydrogen, oxo, halogen, —CX¹⁷ ₃,—CHX¹⁷ ₂, —CH₂X¹⁷, —OCH₂X¹⁷, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹⁷ ₃, —OCHX¹⁷ ₂,R⁷⁸-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁷⁸-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁷⁸-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁷⁸-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁷⁸-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁷⁸-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X¹⁷ is halogen. In embodiments, X¹⁷ is F. In embodiments, R¹⁷ ishydrogen. In embodiments, R¹⁷ is independently hydrogen, halogen, —CX¹⁷₃, —CHX¹⁷ ₂, —CH₂X¹⁷, —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁷⁸ is independently oxo, halogen, —CX⁷⁸ ₃, —CHX⁷⁸ ₂, —CH₂X⁷⁸, —OCH₂X⁷⁸,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁷⁸ ₃, —OCHX⁷⁸ ₂, R⁷⁹-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁷⁹-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁷⁹-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁷⁹-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁷⁹-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁷⁹-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁷⁸ is halogen. Inembodiments, X⁷⁸ is F.

R⁷⁹ is independently oxo, halogen, —CX⁷⁹ ₃, —CHX⁷⁹ ₂, —CH₂X⁷⁹, —OCH₂X⁷⁹,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁷⁹ ₃, —OCHX⁷⁹ ₂, R^(w)-substituted or unsubstituted alkyl(e.g. C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R″-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁸⁰-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁸⁰-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁸⁰-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁸⁰-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁷⁹ is halogen. Inembodiments, X⁷⁹ is F.

In embodiments, R¹⁸ is independently hydrogen, oxo, halogen, —CX¹⁸ ₃,—CHX¹⁸ ₂, —CH₂X¹⁸, —OCH₂X¹⁸, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹⁸ ₃, —OCHX¹⁸ ₂,W^(I)-substituted or unsubstituted alkyl (e.g. C₁-C₈ alkyl, C₁-C₆ alkyl,or C₁-C₄ alkyl), R⁸¹-substituted or unsubstituted heteroalkyl (e.g. 2 to10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), R⁸¹-substituted or unsubstituted cycloalkyl (e.g. C₃-C₈cycloalkyl, C₄-C₈ cycloalkyl, or C₅-C₆ cycloalkyl), R⁸¹-substituted orunsubstituted heterocycloalkyl (e.g. 3 to 8 membered heterocycloalkyl, 4to 8 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),R⁸¹-substituted or unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), orR⁸¹-substituted or unsubstituted heteroaryl (e.g. 5 to 10 memberedheteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).X¹⁸ is halogen. In embodiments, X¹⁸ is F. In embodiments, R¹⁸ ishydrogen. In embodiments, R¹⁸ is independently hydrogen, halogen, —CX¹⁸₃, —CHX¹⁸ ₂, —CH₂X¹⁸, —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

R⁸¹ is independently oxo, halogen, —CX⁸¹ ₃, —CHX⁸¹ ₂, —CH₂X⁸¹, —OCH₂X⁸¹,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁸¹ ₃, —OCHX⁸¹ ₂, R⁸²-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁸²-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁸²-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁸²-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁸²-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁸²-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁸¹ is halogen. Inembodiments, X⁸¹ is F.

R⁸² is independently oxo, halogen, —CX⁸² ₃, —CHX⁸² ₂, —CH₂X⁸², —OCH₂X⁸²,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX⁸² ₃, —OCHX⁸² ₂, R⁸³-substituted or unsubstituted alkyl (e.g.C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), R⁸³-substituted orunsubstituted heteroalkyl (e.g. 2 to 10 membered heteroalkyl, 2 to 8membered heteroalkyl, 4 to 8 membered heteroalkyl, 2 to 6 memberedheteroalkyl, or 2 to 4 membered heteroalkyl), R⁸³-substituted orunsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈ cycloalkyl, orC₅-C₆ cycloalkyl), R⁸³-substituted or unsubstituted heterocycloalkyl(e.g. 3 to 8 membered heterocycloalkyl, 4 to 8 memberedheterocycloalkyl, or 5 to 6 membered heterocycloalkyl), R⁸³-substitutedor unsubstituted aryl (e.g. C₆-C₁₀ aryl or C₆ aryl), or R⁸³-substitutedor unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl, 5 to 9membered heteroaryl, or 5 to 6 membered heteroaryl). X⁸² is halogen. Inembodiments, X⁸² is F.

R³², R³⁵, R³⁸, R⁴¹, R⁴⁴, R⁵⁰, R⁵³, R⁵⁶, R⁵⁹, R⁶², R⁶⁵, R⁶⁸, R⁷¹, R⁷⁴,R⁷⁷, R⁸⁰and R⁸³ are independently hydrogen, oxo, halogen, —CF₃, —CHF₂,—CH₂F, —OCH₂F, —OCF₃, —OCHF₂, —CCl₃, —CHCl₂, —CH₂Cl, —OCH₂Cl, —O CCl₃,—OCHCl₂, —CBr₃, —CHBr₂, —CH₂Br, —OCH₂Br, —OCBr₃, —OCHBr₂, —CI₃, —CHI₂,—CH₂I, —OC H₂I, —OCl₃, —OCHI₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g. 2to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. C₆-C₁₀ aryl orC₆ aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl,5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). Inembodiments, R³², R³⁵, R³⁸, R⁴¹, R⁴⁴, R⁵⁰, R⁵³, R⁵⁶, R⁵⁹, R⁶², R⁶⁵, R⁶⁸,R⁷¹, R⁷⁴, R⁷⁷, R⁸⁰ and R⁸³ are independently oxo, halogen, —CF₃, —CHF₂,—CH₂F, —OCH₂F, —OCF₃, —OCHF₂, —CCl₃, —CHCl₂, —CH₂Cl, —OCH₂Cl, —O CCl₃,—OCHCl₂, —CBr₃, —CHBr₂, —CH₂Br, —OCH₂Br, —OCBr₃, —OCHBr₂, —CI₃, —CHI₂,—CH₂I, —OC H₂I, —OCl_(3,)—OCHI₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, unsubstituted alkyl (e.g. C₁-C₈alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g. 2to 10 membered heteroalkyl, 2 to 8 membered heteroalkyl, 4 to 8 memberedheteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 memberedheteroalkyl), unsubstituted cycloalkyl (e.g. C₃-C₈ cycloalkyl, C₄-C₈cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted heterocycloalkyl (e.g. 3to 8 membered heterocycloalkyl, 4 to 8 membered heterocycloalkyl, or 5to 6 membered heterocycloalkyl), unsubstituted aryl (e.g. C₆-C₁₀ aryl orC₆ aryl), or unsubstituted heteroaryl (e.g. 5 to 10 membered heteroaryl,5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

In some embodiments, the compound is any one of the compounds describedherein (e.g., in an aspect, embodiment, claim, figure, table, orexample).

1,02361 In some embodimnts, a compound as described herein may includemultiple instances of R¹, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and/or other variables. In suchembodiments, each variable may optional be different and beappropriately labeled to distinguish each gro-up for greater clarity.For example, where each R¹, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, and/or R¹⁹ is different, they may be referredto, for example, as R^(1.1), R^(1.2), R^(1.3), R^(1.4), R^(1.5),R^(4.1), R^(4.2), R^(4.3), R^(4.4), R^(4.5), R^(5.1), R^(5.2), R^(5.3),R^(5.4), R^(5.5), R^(5.6), R^(5.7), R^(7.1), R^(7.2), R^(7.3), R^(7.4),R^(7.5), R^(7.6), R^(7.7), R^(7.8), R^(7.9), R^(7.10), R^(7.11),R^(7.12), R^(7.13), R^(7.14), R^(7.15), R¹⁶, R^(7.17), R^(7.18),R^(7.19), R^(7.20), R^(7.21), R^(7.22), R^(7.23), R^(7.24), R^(7.25),R^(7.26), R^(7.27), R^(7.28), R^(7.29), R^(7.30), R^(7.31), R^(7.32),R^(7.33), R^(7.34), R^(7.35), R^(7.36), R^(7.37), R^(7.38), R^(7.39),R^(7.40), R^(7.41), R^(7.42), R^(8.1), R^(8.2), R^(8.3), R^(8.4),R^(8.5), R^(8.6), R^(8.7), R^(8.8), R^(8.9), R^(8.10), R^(8.11),R^(8.12), R^(8.13), R^(8.14), R^(8.15), R^(8.16), R^(8.17), R^(8.18),R^(8.19), R^(8.20), R^(8.21), R^(8.22), R^(8.23), R^(8.24), R^(8.25),R^(8.26), R^(8.27), R^(8.28), R^(8.29), R^(8.30), R^(8.31), R^(8.32),R^(8.33), R^(8.34), R^(8.35), R^(8.36), R^(8.37), R^(8.38), R^(8.39),R^(8.40), R^(8,41), R^(8.42), R^(9.1), R^(9.2), R^(9.3), R^(9.4),R^(9.5), R^(9.6), R^(9.7), R^(9.8), R^(9.9), R^(9.10), R^(9.11),R^(9.12), R^(9.13), R^(9.14), R^(9.15), R^(9.16), R^(9.17), R^(9.18),R^(9.19), R^(9.20), R^(9.21), R^(9.22), R^(9.23), R^(9.24), R^(9.25),R^(9.26), R^(9.27), R^(9.28), R^(9.29), R^(9.30), R^(9.31), R^(9.32),R^(9.33), R^(9.34), R^(9.35), R^(9.36), R^(9.37), R^(9.38), R^(9.39),R^(9.40), R^(9.41), R^(9.42), R^(10.1), R^(10.2), R^(10.3), R^(10.4),R^(10.5), R^(10.6), R^(10.7), R^(10.6), R^(10.8), R^(10.9), R^(10.10),R^(10.11), R^(10.12), R^(10.13), R^(10.14), R^(10.15), R^(10.16),R^(10.17), R^(10.18), R^(10.19), R^(10.20), R^(10.21), R^(10.22),R^(10.23), R^(10.24), R^(10.25), R^(10.26), R^(10.27), R^(10.28),R^(10.29), R^(10.30), R^(10.31), R^(10.32), R^(10.33), R^(10.34),R^(10.35), R^(10.36), R^(10.37), R^(10.38), R^(10.39), R^(10,40),R^(10.41), R^(10.42), R^(11.1), R^(11.2), R^(11.3), R^(11.4), R^(11.5),R^(11.6), R^(11.7), R^(11.8), R^(11.9), R^(11.10), R^(11.11), R^(11.12),R^(11.13), R^(11.14), R^(11.15), R^(11.16), R^(11.17), R^(11.18),R^(11.19), R^(11.20), R^(11.21), R^(11.22), R^(11.23), R^(11.24),R^(11.25), R^(11.26), R^(11.27), R^(11.28), R^(11.29), R^(11.30),R^(11.31), R^(11.32), R^(11.33), R^(11.34), R^(11.35), R^(11.36),R^(11.37), R^(11.38), R^(11.39), R^(11.40), R^(11.41), R^(11.42),R^(12.1), R^(12.2), R^(12.3), R^(12.4), R^(12.5), R^(12.6), R^(12.7),R^(12.8), R^(12.9), R^(12.10), R^(12.11), R^(12.12), R^(12.13),R^(12.14), R^(12.15), R^(12.16), R^(12.17), R^(12.18), R^(12.19),R^(12.20), R^(12.21), R^(12.22), R^(12.23), R^(12.24), R^(12.25),R^(12.26), R^(12.27), R^(12.28), R^(12.29), R^(12.30), R^(12.31),R^(12.32), R^(12.33), R^(12.34), R^(12.35), R^(12.36), R^(12.37),R^(12.38), R^(12.39), R^(12.40), R^(12.41), R^(12.42), R^(13.1),R^(13.2), R^(13.3), R^(13.4), R^(13.5), R^(13.6), R^(13.7), R^(13.8),R^(13.9), R^(13.10), R^(13.11), R^(13.12), R^(13.13), R^(13.14),R^(13.15), R^(13.16), R^(13.17), R^(13.18), R^(13.19), R^(13.20),R^(13.21), R^(13.22), R^(13.23), R^(13.24), R^(13.25), R^(13.26),R^(13.27), R^(13.28), R^(13.29), R^(13.30), R^(13.31), R^(13.32),R^(13.33), R^(13.34), R^(13.35), R^(13.36), R^(13.37), R^(13.38),R^(13.39), R^(13.40), R^(13.41), R^(13.42), R^(14.1), R^(14.2),R^(14.3), R^(14.4), R^(14.5), R^(14.6), R^(14.7), R^(14.8), R^(14.9),R^(14.10), R^(14.11), R^(14.12), R^(14.13), R^(14.14), R^(14.15),R^(14.16), R^(14.17), R^(14.18), R^(14.19), R^(14.20), R^(14.21),R^(14.22), R^(14.23), R^(14.24), R^(14.25), R^(14.26), R^(14.27),R^(14.28), R^(14.29), R^(14.30), R^(14.31), R^(14.32), R^(14.33),R^(14.34), R^(14.35), R^(14.36), R^(14.37), R^(14.38), R^(14.39),R^(14.40), R^(14.41), R^(14.42), R^(15.1), R^(15.2), R^(15.3), R^(15.4),R^(15.5), R^(15.6), R^(15.7), R^(15.5), R^(15.9), R^(15.10), R^(15.11),R^(15.12), R^(15.13), R^(15.14), R^(15.15), R^(15.16), R^(15.17),R^(15.18), R^(15.19), R^(15.20), R^(15.21), R^(15.22), R^(15.23),R^(15.24), R^(15.25), R^(15.26), R^(15.27), R^(15.28), R^(15.29),R^(15.30), R^(15.31), R^(15.32), R^(15.33), R^(15.34), R^(15.35),R^(15.36), R^(15.37), R^(15.38), R^(15.39), R^(15.40), R^(15.41),R^(15.42), R^(16.1), R^(16.2), R^(16.3), R^(16.4), R^(16.5), R^(16.6),R^(16.7), R^(16.8), R^(16.9), R^(16.10), R^(16.11), R^(16.12),R^(16.13), R^(16.14), R^(16.15), R^(16.16), R^(16.17), R^(16.18),R^(16.19), R^(16.20), R^(16.21), R^(16.22), R^(16.23), R^(16.24),R^(16.25), R^(16.26), R^(16.27), R^(16.28), R^(16.29), R^(16.30),R^(16.31), R^(16.32), R^(16.33), R^(16.34), R^(16.35), R^(16.36),R^(16.37), R^(16.38), R^(16.39), R^(16.40), R^(16.41), R^(16.42),R^(17.1), R^(17.2), R^(17.3), R^(17.4), R^(17.5), R^(17.6), R^(17.7),R^(17.8), R^(11.9), R^(17.10), R^(17.11), R^(17.12), R^(17.13),R^(17.14), R^(17.15), R^(17.16), R^(11.17), R^(17.18), R^(17.19),R^(17.20), R^(17.21), R^(17.22), R^(17.23), R^(17.24), R^(17.25),R^(17.26), R^(17.27), R^(17.28), R^(17.29), R^(11.30), R^(17.31),R^(17.32), R^(17.33), R^(17.34), R^(17.35), R^(17.36), R^(17.37),R^(17.38), R^(17.39), R^(17.40), R^(17.41), R^(17.42), R^(18.1),R^(18.2), R^(18.3), R^(18.4), R^(18.5), R^(18.6), R^(18.7), R^(18.8),R^(18.9), R^(18.10), R^(18.11), R^(18.12), R^(18.13), R^(18.14),R^(18.15), R^(18.16), R^(18.17), R^(18.18), R^(18.19), R^(18.20),R^(18.21), R^(18.22), R^(18.23), R^(18.24), R^(18.25), R^(18.26),R^(18.27), R^(18.28), R^(18.29), R^(18.30), R^(18.31), R^(18.32),R^(18.33), R^(18.34), R^(18.35), R^(18.36), R^(18.37), R^(18.35),R^(18.39), R^(18.40), R^(18.41), R^(18.42), respectively, wherein thedefinition of R¹ is assumed by R^(1.1), R^(1.2), R^(1.3), R^(1.4),R^(1.5); R⁴ is assumed by R^(4.1), R^(4.2), R^(4.3), R^(4.4), R^(4.5);R⁵ is assumed by R^(5.1), R^(5.2), R^(5.3), R^(5.4), R^(5.5), R^(5.6),R^(5.7); R⁷ is assumed by R^(7.1), R^(7.2), R^(7.3), R^(7.4), R^(7.5),R^(7.6), R^(7.7), R^(7.8), R^(7.9), R^(7.10), R^(7.11), R^(7.12),R^(7.13), R^(7.14), R^(7.15), R^(7.16), R^(7.17), R^(7.18), R^(7.19),R^(7.20), R^(7.21), R^(7.22), R^(7.23), R^(7.24), R^(7.25), R^(7.26),R^(7.27), R^(7.25), R^(7.29), R^(7.30), R^(7.31), R^(7.32), R^(7.33),R^(7.34), R^(7.35), R^(7.36), R^(7.37), R^(7.38), R^(7.39), R^(7.40),R^(7.41), R^(7.42); R⁸ is assumed by R^(8.1), R^(8.2), R^(8.3), R^(8.4),R^(8.5), R^(8.6), R^(8.7), R^(8.8), R^(8.9), R^(8.10), R^(8.11),R^(8.12), R^(8.13), R^(8.14), R^(8.15), R^(8.16), R^(8.17), R^(8.18),R^(8.19), R^(8.20), R^(8.21), R^(8.22), R^(8.23), R^(8.24), R^(8.25),R^(8.26), R^(8.27), R^(8.28), R^(8.29), R^(8.30), R^(8.31), R^(8.32),R^(8.33), R^(8.34), R^(8.35), R^(8.36), R^(8.37), R^(8.38), R^(8.39),R^(8.40), R^(8.41), R^(8.42); R⁹ is assumed by R^(9.1.), R^(9.2),R^(9.3), R^(9.4), R^(9.5), R^(9.6), R^(9.7), R^(9.8), R^(9.9), R^(9.10),R^(9.11), R^(9.12), R^(9.13), R^(9.14), R^(9.15), R^(9.16), R^(9.17),R^(9.17), R^(9.19), R^(9.20), R^(9.21), R^(9.22), R^(9.23), R^(9.24),R^(9.25), R^(9.26), R^(9.27), R^(9.28), R^(9.29), R^(9.30), R^(9.31),R^(9.32), R^(9.33), R^(9.34), R^(9.35), R^(9.36), R^(9.37), R^(9.38),R^(9.39), R^(9.40), R^(9.41), R^(9.42); R¹⁰ is assumed by R^(10.1),R^(10.2), R^(10.3), R^(10.4), R^(10.5), R^(10.6), R^(10.7), R^(10.8),R^(10.9), R^(10.10), R^(10.11), R^(10.12), R^(10.13), R^(10.14),R^(10.15), R^(10.16), R^(10.17), R^(10.18), R^(10.19), R^(10.20),R^(10.21), R^(10.22), R^(10.23), R^(10.24), R^(10.25), R^(10.26),R^(10.27), R^(10.28), R^(10.29), R^(10.30), R^(10.31), R^(10.32),R^(10.33), R^(10.34), R^(10.35), R^(10.36), R^(10.37), R^(10.38),R^(10.39), R^(10.40), R^(10.41), R^(10.42.); R¹¹ is assumed by R^(11.1),R^(11.2), R^(11.3), R^(11.4), R^(11.5), R^(11.6), R^(11.7), R^(11.8),R^(11.9), R^(11.10), R^(11.11), R^(11.12), R^(11.13), R^(11.14),R^(11.15), R^(11.16), R^(11.17), R^(11.18), R^(11.19), R^(11.20),R^(11.21), R^(11.22), R^(11.23), R^(11.24), R^(11.25), R^(11.26),R^(11.27), R^(11.28), R^(11.29), R^(11.30), R^(11.31), R^(11.32),R^(11.33), R^(11.34), R^(11.35), R^(11.36), R^(11.37), R^(11.38),R^(11.39), R^(11.40), R^(11.41), R^(11.42); R¹² is assumed by R^(12.1),R^(12.2), R^(12.3), R^(12.4), R^(12.5), R^(12.6), R^(12.7), R^(12.8),R^(12.9), R^(12.10), R^(12.11), R^(12.12), R^(12.13), R^(12.14),R^(12.15), R^(12.16), R^(12.17), R^(12.18), R^(12.19), R^(12.20),R^(12.21), R^(12.22), R^(12.23), R^(12.24), R^(12.25), R^(12.26),R^(12.27), R^(12.28), R^(12.29), R^(12.30), R^(12.31), R^(12.32),R^(12.33), R^(12.34), R^(12.35), R^(12.36), R^(12.37), R^(12.38),R^(12.39), R^(12.40), R^(12.41), R^(12.42); R¹³ is assumed by R^(13.1),R^(13.2), R^(13.3), R^(13.4), R^(13.5), R^(13.6), R^(13.7), R^(13.8),R^(13.9), R^(13.10), R^(13.11), R^(13.12), R^(13.13), R^(13.14),R^(13.15), R^(13.16), R^(13.17), R^(13.18), R^(13.19), R^(13.20),R^(13.21), R^(13.22), R^(13.23), R^(13.24), R^(13.25), R^(13.26),R^(13.27), R^(13.28), R^(13.29), R^(13.30), R^(13.31), R^(13.32),R^(13.33), R^(13.34), R^(13.35), R^(13.36), R^(13.37), R^(13.38),R^(13.39), R^(13.40), R^(13.41), R^(13.42); R¹⁴ is assumed by R^(14.1),R^(14.2), R^(14.3), R^(14.4), R^(14.5), R^(14.6), R^(14.7), R^(14.8),R^(1.9), R^(14.10), R^(14.11), R^(14.12), R^(14.13), R^(14.14),R^(14.15), R^(14.16), R^(14.17), R^(14.18), R^(14.19), R^(14.20),R^(14.21), R^(14.22), R^(14.23), R^(14.24), R^(14.25), R^(14.26),R^(14.27), R^(14.28), R^(14.29), R^(14.30), R^(14.31), R^(14.32),R^(14.33), R^(14.34), R^(14.35), R^(14.36), R^(14.37), R^(14.38),R^(14.39), R^(14.40), R^(14.41), R^(14.42); R¹⁵ is assumed by R^(15.1),R^(15.2), R^(15.3), R^(15.4), R^(15.5), R^(15.6), R^(15.7), R^(15.8),R^(15.9), R^(15.10), R^(15.11), R^(15.12), R^(15.13), R^(15.14),R^(15.15), R^(15.16), R^(15.17), R^(15.18), R^(15.19), R^(15.20),R^(15.21), R^(15.22), R^(15.23), R^(15.24), R^(15.25), R^(15.26),R^(15.27), R^(15.28), R^(15.29), R^(15.30), R^(15.31), R^(15.32),R^(15.33), R^(15.34), R^(15.35), R^(15.36), R^(15.37), R^(15.38),R^(15.39), R^(15.40), R^(15.41), R^(15.42); R¹⁶ is assumed by R^(16.1),R^(16.2), R^(16.3), R^(16.4), R^(16.5), R^(16.6), R^(16.7), R^(16.8),R^(16.9), R^(16.10), R^(16.11), R^(16.12), R^(16.13), R^(16.14),R^(16.15), R^(16.16), R^(16.17), R^(16.18), R^(16.19), R^(16.20),R^(16.21), R^(16.22), R^(16.23), R^(16.24), R^(16.25), R^(16.26),R^(16.27), R^(16.28), R^(16.29), R^(16.30), R^(16.31), R^(16.32),R^(16.33), R^(16.34), R^(16.35), R^(16.36), R^(16.37), R^(16.38),R^(16.39), R^(16.40), R^(16.41), R^(16.42); R¹⁷ is assumed by R^(17.1),R^(17.2), R^(17.3), R^(17.4), R^(17.5), R^(17.6), R^(17.7), R^(17.8),R^(17.9), R^(17.10), R^(17.11), R^(17.12), R^(17.13), R^(17.14),R^(17.15), R^(17.16), R^(11.17), R^(17.18), R^(17.19), R^(17.20),R^(17.21), R^(17.22), R^(17.23), R^(17.24), R^(17.25), R^(17.26),R^(17.27), R^(17.28), R^(17.29), R^(17.30), R^(17.31), R^(17.32),R^(17.33), R^(17.34), R^(17.35), R^(17.36), R^(17.37), R^(17.38),R^(17.39), R^(17.40), R^(17.41), R^(17.42); and/or R¹⁸ is assumed byR^(18.1), R^(18.2), R^(18.3), R^(18.4), R^(18.5), R^(18.6), R^(18.7),R^(18.8), R^(18.9), R^(18.10), R^(18.11), R^(18.12), R^(18.13),R^(18.14), R^(18.15), R^(18.16), R^(18.17), R^(18.18), R^(18.19),R^(18.20), R^(18.21), R^(18.22), R^(18.23), R^(18.24), R^(18.25),R^(18.26), R^(18.27), R^(18.28), R^(18.29), R^(18.30), R^(18.31),R^(18.32), R^(18.33), R^(18.34), R^(18.35), R^(18.36), R^(18.37),R^(18.38), R^(18.39), R^(18.40), R^(18.41), R^(18.42). The variablesused within a definition of R¹, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and/or other variables that appear atmultiple instances and are different may similarly be appropriatelylabeled to distinguish each group for greater clarity. In someembodiments, the compound is a compound described herein (e.g., in anaspect, embodiment, example, claim, table, scheme, drawaing, or figure).

In embodiments, the compound has the formula:

R², R³, R⁵, and z3 are as described herein, including in compounds offormula (I) to (V). R^(1.1), R^(1.2), and R^(1.3) are each independentlya moiety of R¹ as described herein, including in embodiments. R^(4.1),R^(4.2), and R^(4.3) are each independently a moiety of R⁴ as describedherein, including in embodiments. In embodiment, z3 is 0. Inembodiments, one or more of R^(1.1), R^(1.2), R^(1.3), R^(4.1), R^(4.2),R^(4.3), R² and/or R³ are hydrogen. In embodiments, R^(1.1), R^(1.2),and/or R^(1.3) are hydrogen. In embodiments, R^(4.1), R^(4.2) and/orR^(4.3) are hydrogen. In embodiments, R² is hydrogen. In embodiments, R³is hydrogen. In embodiments, R^(4.1) is hydrogen, R^(4.2) is —OH, andR^(4.3) is hydrogen. In embodiments, R^(4.1) is hydrogen, R^(4.2) ishydrogen, and R^(4.3) is —OH. In embodiments, R^(4.1) is hydrogen,R^(4.2) is unsubstituted methoxy, and R^(4.3) is hydrogen. Inembodiments, R^(4.1) is hydrogen, R^(4.2) is hydrogen, and R^(4.3) isunsubstituted methoxy. It will be understood that R⁵ is/are a floatingsubstituent and may be positioned on either or both rings.

In embodiments, the compound has the formula:

R², R³, R⁵, and z3 are as described herein, including in compounds offormula (I) to (V). It will be understood that R⁵ is/are a floatingsubstituent and may be positioned on either or both rings. R^(1.1),R^(1.2), and/or R^(1.3) are each independently a moiety of R¹ asdescribed herein, including in embodiments. R^(4.1) and R^(4.3) are eachindependently a moiety of R⁴ as described herein, including inembodiments.

W¹ is N or C(R^(4.2)). W² is N or C(R^(5.1)). W³ is N or C(R^(5.2)).R^(5.1) and R^(5.2) are each independently a moiety of R⁵ as describedherein, including in embodiments. R^(4.2) is independently a moiety ofR⁴ as described herein, including in embodiments. In embodiments, W¹ isN. In embodiments, W² is N. In embodiments, W³ is N. In embodiments, W¹is C(R^(4.2)). In embodiments, W² is C(R^(5.1)). In embodiments, W³ isC(R^(5.2)). In embodiments, W¹ is CH. In embodiments, W² is CH. Inembodiments, W³ is CH.

In embodiments, the compound has the formula:

R², R³, R⁵, and z3 are as described herein, including in compounds offormula (I) to (V). It will be understood that R⁵ is/are a floatingsubstituent and may be positioned on either or both rings. R^(1.1) andR^(1.3) are each independently a moiety of R¹ as described herein,including in embodiments. R^(4.1) and R^(4.3) are each independently amoiety of R⁴ as described herein, including in embodiments.

In embodiments, the compound has the formula:

R², R³, R⁵, and z3 are as described herein, including in compounds offormula (I) to (V). It will be understood that R⁵ is/are a floatingsubstituent and may be positioned on either or both rings. R^(1.1) andR^(1.3) are each independently a moiety of R¹ as described herein,including in embodiments. R^(4.1), R^(4.2), and R^(4.3) are eachindependently a moiety of R⁴ as described herein, including inembodiments.

In embodiments, the compound has the formula:

R², R³, R⁵, and z3 are as described herein, including in compounds offormula (I) to (V). It will be understood that R⁵ is/are a floatingsubstituent and may be positioned on either or both rings. R^(1.1) andR^(1.3) are each independently a moiety of R¹ as described herein,including in embodiments. R^(1.1) and R^(1.3) are each independently amoiety of R⁴ as described herein, including in embodiments.

W¹ is N or C(R^(4.1)) W² is N or C(R^(5.1)). W³ is N or C(R^(5.2)).R^(5.1) and R^(5.2) are each independently a moiety of R⁵ as describedherein, including in embodiments. R^(4.2) is independently a moiety ofR⁴ as described herein, including in embodiments. In embodiments, W¹ isN. In embodiments, W² is N. In embodiments, W³ is N. In embodiments, W¹is C(R^(4.2)). In embodiments, W² is C(R^(5.1)). In embodiments, W³ isC(R^(5.2)). In embodiments, W¹ is CH. In embodiments, W² is CH. Inembodiments, W³ is CH.

In embodiments of the compounds of formula (VI) to (X), R² is hydrogen.In embodiments of the compounds of formula (VI) to (X), R³ is hydrogen.In embodiments of the compounds of formula (VI) to (X), R² and R³ arehydrogen.

In embodiments, R^(1.1) is independently halogen. In embodiments,R^(1.1) is independently —CF₃. In embodiments, R^(1.1) is independently—CHF₂. In embodiments, R^(1.1) is independently —CH₂F. In embodiments,R^(1.1) is independently —OCF₃. In embodiments, R^(1.1) is independently—OCHF₂. In embodiments, R^(1.1) is independently —OCH₂F. In embodiments,R^(1.1) is independently —OH. In embodiments, R^(1.1) is independently—NH₂. In embodiments, R^(1.1) is independently —SH. In embodiments,R^(1.1) is independently substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R^(1.1) is independently substituted or unsubstituted 2 to4 membered heteroalkyl. In embodiments, R^(1.1) is independentlysubstituted or unsubstituted C₃-C₆ cycloalkyl. In embodiments, R^(1.1)is independently substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. In embodiments, R^(1.1) is independently substitutedor unsubstituted phenyl. In embodiments, R^(1.1) is independentlysubstituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments,R^(1.1) is independently substituted C₁-C₄ alkyl. In embodiments,R^(1.1) is independently substituted to 4 membered heteroalkyl. Inembodiments, R^(1.1) is independently substituted C₃-C₆ cycloalkyl. Inembodiments, R^(1.1) is independently substituted 3 to 6 memberedheterocycloalkyl. In embodiments, R^(1.1) is independently substitutedphenyl. In embodiments, R^(1.1) is independently substituted 5 to 6membered heteroaryl. In embodiments, R^(1.1) is independentlyunsubstituted C₁-C₄ alkyl. In embodiments, R^(1.1) is independentlyunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(1.1) isindependently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R^(1.1) isindependently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R^(1.1) is independently unsubstituted phenyl. Inembodiments, R^(1.1) is independently unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R^(1.1) is independently unsubstitutedmethyl. In embodiments, R^(1.1) is independently unsubstituted ethyl. Inembodiments, R^(1.1) is independently unsubstituted isopropyl. Inembodiments, R^(1.1) is independently unsubstituted tert-butyl. Inembodiments, R^(1.1) is independently unsubstituted methoxy. Inembodiments, R^(1.1) is independently unsubstituted ethoxy. Inembodiments, R^(1.1) is independently —F. In embodiments, R^(1.1) isindependently —Cl. In embodiments, R^(1.1) is independently —Br. Inembodiments, R^(1.1) is independently —I. In embodiments, R^(1.1) isindependently hydrogen.

In embodiments, R^(1.2) is independently halogen. In embodiments,R^(1.2) is independently —CF₃. In embodiments, R^(1.2) is independently—CHF₂. In embodiments, R^(1.2) is independently —CH₂F. In embodiments,R^(1.2) is independently —OCF₃. In embodiments, R^(1.2) is independently—OCHF₂. In embodiments, R^(1.2) is independently —OCH₂F. In embodiments,R^(1.2) is independently —OH. In embodiments, R^(1.2) is independently—NH₂. In embodiments, R^(1.2) is independently —SH. In embodiments,R^(1.2) is independently substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R^(1.2) is independently substituted or unsubstituted 2 to4 membered heteroalkyl. In embodiments, R^(1.2) is independentlysubstituted or unsubstituted C₃-C₆ cycloalkyl. In embodiments, R^(1.2)is independently substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. In embodiments, R^(1.2) is independently substitutedor unsubstituted phenyl. In embodiments, R^(1.2) is independentlysubstituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments,R^(1.2) is independently substituted C₁-C₄ alkyl. In embodiments,R^(1.2) is independently substituted to 4 membered heteroalkyl. Inembodiments, R^(1.2) is independently substituted C₃-C₆ cycloalkyl. Inembodiments, R^(1.2) is independently substituted 3 to 6 memberedheterocycloalkyl. In embodiments, R^(1.2) is independently substitutedphenyl. In embodiments, R^(1.2) is independently substituted 5 to 6membered heteroaryl. In embodiments, R^(1.2) is independentlyunsubstituted C₁-C₄ alkyl. In embodiments, R^(1.2) is independentlyunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(1.2) isindependently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R^(1.2) isindependently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R^(1.2) is independently unsubstituted phenyl. Inembodiments, R^(1.2) is independently unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R^(1.2) is independently unsubstitutedmethyl. In embodiments, R^(1.2) is independently unsubstituted ethyl. Inembodiments, R^(1.2) is independently unsubstituted isopropyl. Inembodiments, R^(1.2) is independently unsubstituted tert-butyl. Inembodiments, R^(1.2) is independently unsubstituted methoxy. Inembodiments, R^(1.2) is independently unsubstituted ethoxy. Inembodiments, R^(1.2) is independently —F. In embodiments, R^(1.2) isindependently —Cl. In embodiments, R^(1.2) is independently —Br. Inembodiments, R^(1.2) is independently —I. In embodiments, R^(1.2) isindependently hydrogen.

In embodiments, R^(1.3) is independently halogen. In embodiments,R^(1.3) is independently —CF₃. In embodiments, R^(1.3) is independently—CHF₂. In embodiments, R^(1.3) is independently —CH₂F. In embodiments,R^(1.3) is independently —OCF₃. In embodiments, R^(1.3) is independently—OCHF₂. In embodiments, R^(1.3) is independently —OCH₂F. In embodiments,R^(1.3) is independently —OH. In embodiments, R^(1.3) is independently—NH₂. In embodiments, R^(1.3) is independently —SH. In embodiments,R^(1.3) is independently substituted or unsubstituted C₁-C₄ alkyl. Inembodiments, R^(1.3) is independently substituted or unsubstituted 2 to4 membered heteroalkyl. In embodiments, R^(1.3) is independentlysubstituted or unsubstituted C₃-C₆ cycloalkyl. In embodiments, R^(1.3)is independently substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. In embodiments, R^(1.3) is independently substitutedor unsubstituted phenyl. In embodiments, R^(1.3) is independentlysubstituted or unsubstituted 5 to 6 membered heteroaryl. In embodiments,R^(1.3) is independently substituted C₁-C₄ alkyl. In embodiments,R^(1.3) is independently substituted to 4 membered heteroalkyl. Inembodiments, R^(1.3) is independently substituted C₃-C₆ cycloalkyl. Inembodiments, R^(1.3) is independently substituted 3 to 6 memberedheterocycloalkyl. In embodiments, R^(1.3) is independently substitutedphenyl. In embodiments,

R″3 is independently substituted 5 to 6 membered heteroaryl. Inembodiments, R^(1.3) is independently unsubstituted C₁-C₄ alkyl. Inembodiments, R^(1.3) is independently unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R^(1.3) is independently unsubstitutedC₃-C₆ cycloalkyl. In embodiments, R^(1.3) is independently unsubstituted3 to 6 membered heterocycloalkyl. In embodiments, R^(1.3) isindependently unsubstituted phenyl. In embodiments, R^(1.3) isindependently unsubstituted 5 to 6 membered heteroaryl. In embodiments,R^(1.3) is independently unsubstituted methyl. In embodiments, R^(1.3)is independently unsubstituted ethyl. In embodiments, R^(1.3) isindependently unsubstituted isopropyl. In embodiments, R^(1.3) isindependently unsubstituted tert-butyl. In embodiments, R^(1.3) isindependently unsubstituted methoxy. In embodiments, R^(1.3) isindependently unsubstituted ethoxy. In embodiments, R^(1.3) isindependently —F. In embodiments, R^(1.3) is independently —Inembodiments, R^(1.3) is independently —Br. In embodiments, R^(1.3) isindependently —I. In embodiments, R^(1.3) is independently hydrogen.

In embodiments, R^(1.4) is independently halogen. In embodiments,R^(1.4) is independently —CF₃. In embodiments, R^(1.4) is independently—CHF₂. In embodiments, R^(1.4) is independently —CH₂F. In embodiments,R^(1.4) is independently —OCF₃. In embodiments, R^(1.4) is independently—OCHF₂. In embodiments, R^(1.4) is independently —OCH₂F. In embodiments,R″ is independently —OH. In embodiments, R^(1.4) is independently —NH₂.In embodiments, R^(1.4) is independently —SH. In embodiments, R^(1.4) isindependently substituted or unsubstituted C₁-C₄ alkyl. In embodiments,R^(1.4) is independently substituted or unsubstituted 2 to 4 memberedheteroalkyl. In embodiments, R^(1.4) is independently substituted orunsubstituted C₃-C₆ cycloalkyl. In embodiments, R^(1.4) is independentlysubstituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R^(1.4) is independently substituted or unsubstitutedphenyl. In embodiments, R^(1.4) is independently substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(1.4) isindependently substituted C₁-C₄ alkyl. In embodiments, R^(1.4) isindependently substituted to 4 membered heteroalkyl. In embodiments,R^(1.4) is independently substituted C₃-C₆ cycloalkyl. In embodiments,R^(1.4) is independently substituted 3 to 6 membered heterocycloalkyl.In embodiments, R^(1.4) is independently substituted phenyl. Inembodiments, R^(1.4) is independently substituted 5 to 6 memberedheteroaryl. In embodiments, R^(1.4) is independently unsubstituted C₁-C₄alkyl. In embodiments, R^(1.4) is independently unsubstituted 2 to 4membered heteroalkyl. In embodiments, R^(1.4) is independentlyunsubstituted C₃-C₆ cycloalkyl. In embodiments, R^(1.4) is independentlyunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R^(1.4)is independently unsubstituted phenyl. In embodiments, R^(1.4) isindependently unsubstituted 5 to 6 membered heteroaryl. In embodiments,R^(1.4) is independently unsubstituted methyl. In embodiments, R^(1.4)is independently unsubstituted ethyl.

In embodiments, R^(1.4) is independently unsubstituted isopropyl. Inembodiments, R^(1.4) is independently unsubstituted tert-butyl. Inembodiments, R^(1.4) is independently unsubstituted methoxy. Inembodiments, R^(1.4) is independently unsubstituted ethoxy. Inembodiments, R^(1.4) is independently —F. In embodiments, R^(1.4) isindependently —Cl. In embodiments, R^(1.4) is independently —Br. Inembodiments, R^(1.4) is independently —I. In embodiments, R^(1.4) isindependently hydrogen.

In embodiments, R^(4.1) is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(4.1) isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(4.1) isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R^(4.1) is independently halogen. Inembodiments, R^(4.1) is independently —OH. In embodiments, R^(4.1) isindependently unsubstituted methyl. In embodiments, R^(4.1) isindependently unsubstituted methoxy. In embodiments, R^(4.1) isindependently unsubstituted ethyl. In embodiments, R^(4.1) isindependently —F. In embodiments, R^(4.1) is independently —Cl. Inembodiments, R^(4.1) is independently —Br. In embodiments, R^(4.1) isindependently —I. In embodiments, R^(4.1) is independently —CF₃. Inembodiments, R^(4.1) is independently —NH₂. In embodiments, R^(4.1) isindependently —SH. In embodiments, R^(4.1) is independently hydrogen. Inembodiments, R^(4.1) is independently unsubstituted isopropyl. Inembodiments, R^(4.1) is independently unsubstituted ethoxy. Inembodiments, R^(4.1) is independently unsubstituted tert-butyl. Inembodiments, R^(4.1) is independently unsubstituted propoxy.

In embodiments, R^(4.2) is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(4.2) isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(4.2) isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R^(4.2) is independently halogen. Inembodiments, R^(4.2) is independently —OH. In embodiments, R^(4.2) isindependently unsubstituted methyl. In embodiments, R^(4.2) isindependently unsubstituted methoxy. In embodiments, R^(4.2) isindependently unsubstituted ethoxy. In embodiments, R^(4.2) isindependently unsubstituted ethyl. In embodiments, R^(4.2) isindependently —F. In embodiments, R^(4.2) is independently —Cl. Inembodiments, R^(4.2) is independently —Br. In embodiments, R^(4.2) isindependently —I. In embodiments, R^(4.2) is independently —CF₃. Inembodiments, R^(4.2) is independently —NH₂. In embodiments, R^(4.2) isindependently —SH. In embodiments, R^(4.2) is independently hydrogen. Inembodiments, R^(4.2) is independently unsubstituted isopropyl. Inembodiments, R^(4.2) is independently unsubstituted ethoxy. Inembodiments, R^(4.2) is independently unsubstituted tert-butyl. Inembodiments, R^(4.2) is independently unsubstituted propoxy.

In embodiments, R^(4.3) is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(4.3) isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(4.3) isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R^(4.3) is independently halogen. Inembodiments, R^(4.3) is independently —OH. In embodiments, R^(4.3) isindependently unsubstituted methyl. In embodiments, R^(4.3) isindependently unsubstituted methoxy. In embodiments, R^(4.3) isindependently unsubstituted ethyl. In embodiments, R^(4.3) isindependently —F. In embodiments, R^(4.3) is independently —Cl. Inembodiments, R^(4.3) is independently —Br. In embodiments, R^(4.3) isindependently —I. In embodiments, R^(4.3) is independently —CF₃. Inembodiments, R^(4.3) is independently —NH₂. In embodiments, R^(4.3) isindependently —SH. In embodiments, R^(4.3) is independently hydrogen. Inembodiments, R^(4.3) is independently unsubstituted isopropyl. Inembodiments, R^(4.3) is independently unsubstituted ethoxy. Inembodiments, R^(4.3) is independently unsubstituted tert-butyl. Inembodiments, R^(4.3) is independently unsubstituted propoxy.

In embodiments, R^(4.4) is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(4.4) isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(4.4) isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R^(4.4) is independently halogen. Inembodiments, R^(4.4) is independently —OH. In embodiments, R^(4.4) isindependently unsubstituted methyl. In embodiments, R^(4.4) isindependently unsubstituted methoxy. In embodiments, R^(4.4) isindependently unsubstituted ethyl. In embodiments, R^(4.4) isindependently —F. In embodiments, R^(4.4) is independently —Cl. Inembodiments, R^(4.4) is independently —Br. In embodiments, R^(4.4) isindependently —I. In embodiments, R^(4.4) is independently —CF₃. Inembodiments, R^(4.4) is independently —NH₂. In embodiments, R^(4.4) isindependently —SH. In embodiments, R^(4.4) is independently hydrogen. Inembodiments, R^(4.4) is independently unsubstituted isopropyl. Inembodiments, R^(4.4) is independently unsubstituted ethoxy. Inembodiments, R^(4.4) is independently unsubstituted tert-butyl. Inembodiments, R^(4.4) is independently unsubstituted propoxy.

In embodiments, R^(4.5) is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(4.5) isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(4.5) isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R^(4.5) is independently halogen. Inembodiments, R^(4.5) is independently —OH. In embodiments, R^(4.5) isindependently unsubstituted methyl. In embodiments, R^(4.5) isindependently unsubstituted methoxy. In embodiments, R^(4.5) isindependently unsubstituted ethyl. In embodiments, R^(4.5) isindependently —F. In embodiments, R^(4.5) is independently —Cl. Inembodiments, R^(4.5) is independently —Br. In embodiments, R^(4.5) isindependently —I. In embodiments, R^(4.5) is independently —CF₃. Inembodiments, R^(4.5) is independently —NH₂. In embodiments, R^(4.5) isindependently —SH. In embodiments, R^(4.5) is independently hydrogen. Inembodiments, R^(4.5) is independently unsubstituted isopropyl. Inembodiments, R^(4.5) is independently unsubstituted ethoxy. Inembodiments, R^(4.5) is independently unsubstituted tert-butyl. Inembodiments, R^(4.5) is independently unsubstituted propoxy.

In embodiments, R^(5.1) is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(5.1) isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(5.1) isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R^(5.1) is independently halogen. Inembodiments, R^(5.1) is independently —OH. In embodiments, R^(5.1) isindependently unsubstituted methyl. In embodiments, R^(5.1) isindependently unsubstituted methoxy. In embodiments, R^(5.1) isindependently unsubstituted ethyl. In embodiments, R^(5.1) isindependently —F. In embodiments, R^(5.1) is independently —Cl. Inembodiments, R^(5.1) is independently —Br. In embodiments, R^(5.1) isindependently —I. In embodiments, R^(5.1) is independently —CF₃. Inembodiments, R^(5.1) is independently —NH₂. In embodiments, R^(5.1) isindependently —SH. In embodiments, R^(5.1) is independently hydrogen. Inembodiments, R^(5.1) is independently unsubstituted isopropyl. Inembodiments, R^(5.1) is independently unsubstituted ethoxy. Inembodiments, R^(5.1) is independently unsubstituted tert-butyl. Inembodiments, R^(5.1) is independently unsubstituted propoxy.

In embodiments, R^(5.2) is independently halogen, —CF₃, —OH, —NH₂, —SH,substituted or unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2to 4 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R^(5.2) isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R^(5.2) isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy. In embodiments, R^(5.2) is independently halogen. Inembodiments, R^(5.2) is independently —OH. In embodiments, R^(5.2) isindependently unsubstituted methyl. In embodiments, R^(5.2) isindependently unsubstituted methoxy. In embodiments, R^(5.2) isindependently unsubstituted ethyl. In embodiments, R^(5.2) isindependently —F. In embodiments, R^(5.2) is independently —Cl. Inembodiments, R^(5.2) is independently —Br. In embodiments, R^(5.2) isindependently —I. In embodiments, R^(5.2) is independently —CF₃. Inembodiments, R^(5.2) is independently —NH₂. In embodiments, R^(5.2) isindependently —SH. In embodiments, R^(5.2) is independently hydrogen. Inembodiments, R^(5.2) is independently unsubstituted isopropyl. Inembodiments, R^(5.2) is independently unsubstituted ethoxy. Inembodiments, R^(5.2) is independently unsubstituted tert-butyl. Inembodiments, R^(5.2) is independently unsubstituted propoxy.

In embodiments, W¹ is N. In embodiments, W¹ is C(R^(4.2)). Inembodiments, W² is N. In embodiments, W² is C(R^(5.1)). In embodiments,W³ is N. In embodiments, W³ is C(R^(5.2)). In embodiments, W¹ is C(H).In embodiments, W² is C(H). In embodiments, W³ is C(H).

In embodiments, R^(1.1) and R^(1.3) are —I. In embodiments, R^(1.1) andR^(1.3) are —F. In embodiments, R^(1.1) and R^(1.3) are —Br. Inembodiments, R^(1.1) and R^(1.3) are —Cl. In embodiments, R^(1.1) andR^(1.3) are unsubstituted methyl. In embodiments, R^(1.1) and R^(1.3)are —CF₃. In embodiments, R^(1.1) and R^(1.3) are —NH₂. In embodiments,R^(1.1) and R^(1.3) are —OH. In embodiments, R^(1.1) and R^(1.3) areunsubstituted methoxy. In embodiments, R^(1.1) and R^(1.3) are halogen.In embodiments, R^(1.1) and R^(1.3) are unsubstituted C₁-C₄ alkyl. Inembodiments, R^(1.1) and R^(1.3) are substituted C₁-C₄ alkyl. Inembodiments, R^(1.1) and R^(1.3) are halogen substituted C₁-C₄ alkyl. Inembodiments, R^(1.1) and R^(1.3) are unsubstituted C₁-C₂ alkyl. Inembodiments, R^(1.1) and R^(1.3) are substituted C₁-C₂ alkyl. Inembodiments, R^(1.1) and R^(1.3) are halogen substituted C₁-C₂ alkyl.

In embodiments, R^(4.1) and R^(4.3) are I. In embodiments, R^(4.1) andR^(4.3) are F. In embodiments, R^(4.1) and R^(4.3) are Br. Inembodiments, R^(4.1) and R^(4.3) are Cl. In embodiments, R^(4.1) andR^(4.3) are unsubstituted methyl. In embodiments, R^(4.1) and R^(4.3)are —CF₃. In embodiments, R^(4.1) and R^(4.3) are —NH₂. In embodiments,R^(4.1) and R^(4.3) are —OH. In embodiments, R^(4.1) and R^(4.3) areunsubstituted methoxy. In embodiments, R^(4.1) and R^(4.3) are halogen.In embodiments, R^(4.1) and R^(4.3) are unsubstituted C₁-C₄ alkyl. Inembodiments, R^(4.1) and R^(4.3) are substituted C₁-C₄ alkyl. Inembodiments, R^(4.1) and R^(4.3) are halogen substituted C₁-C₄ alkyl. Inembodiments, R^(4.1) and R^(4.3) are unsubstituted C₁-C₂ alkyl. Inembodiments, R^(4.1) and R^(4.3) are substituted C₁-C₂ alkyl. Inembodiments, R^(4.1) and R^(4.3) are halogen substituted C₁-C₂ alkyl.

In embodiments, the compound has the formula:

R², R³, R⁵, and z3 are as described herein, including in compounds offormula (I) to (V). R^(1.1), R^(1.2), R^(1.3), and R^(1.4) are eachindependently a moiety of R¹ as described herein, including inembodiments. In embodiments, R^(1.1), R^(1.2), R^(1.3), and/or R^(1.4)are hydrogen. In embodiments, R^(4.1), R^(4.2), R^(4.3), R^(4.4), and/orR^(4.5) are hydrogen. In embodiments, R² is hydrogen. In embodiments, R³is hydrogen. In embodiments R^(1.4) is halogen. In embodiments R^(1.2)is halogen. In embodiments R^(1.3) is halogen. In embodiments R^(1.4) ishalogen. In embodiments R^(1.4) is —Cl. In embodiments R^(1.2) is —Cl.In embodiments R^(1.3) is —Cl. In embodiments R^(1.1) is —Cl. Inembodiments R¹⁴ is —F. In embodiments R^(1.2) is —F. In embodimentsR^(1.3) is —F. In embodiments R^(1.4) is —F. In embodiments R^(1.2),R^(1.3), and R^(1.4) are hydrogen and R^(1.4) is halogen. In embodimentsR^(1.3), and R^(1.4) are hydrogen and R^(1.2) is halogen. In embodimentsR^(1.2), R^(1.1), and R^(1.4) are hydrogen and R^(1.3) is halogen. Inembodiments R^(1.2), R^(1.3), and R^(1.1) are hydrogen and R^(1.4) ishalogen. In embodiments R^(1.2), R^(1.3), and R^(1.4) are hydrogen andR¹⁴ is —Cl. In embodiments R^(1.1), R^(1.3), and R^(1.4) are hydrogenand R^(1.2) is —Cl. In embodiments R^(1.2), R^(1.1), and R^(1.4) arehydrogen and R^(1.3) is —Cl. In embodiments R^(1.2), R^(1.3), andR^(1.1) are hydrogen and R^(1.4) is —Cl. In embodiments R^(1.2),R^(1.3), and R^(1.4) are hydrogen and R^(1.1) is —F. In embodimentsR^(1.1), R^(1.3), and R^(1.4) are hydrogen and R^(1.2) is —F. Inembodiments R^(1.2), R^(1.1), and R^(1.4) are hydrogen and R^(1.3) is—F. In embodiments R^(1.2), R^(1.3), and R^(1.1) are hydrogen andR^(1.4) is —F. W¹ is N or C(R^(4.2)). W² is N or C(R^(5.1)). W³ is N orC(R^(5.2)). In embodiments, W¹ is N. In embodiments, W² is N. Inembodiments, W³ is N. In embodiments, W¹ is C(R^(4.2)). In embodiments,W² is C(R^(5.1)). In embodiments, W³ is C(R^(5.2)). In embodiments, W¹is CH. In embodiments, W² is CH. In embodiments, W³ is CH. R^(5.1) andR^(5.2) are each independently a moiety of R⁵ as described herein,including in embodiments. In embodiment, z3 is 0. R^(4.1), R^(4.2),R^(4.3), R^(4.4) and R^(4.5) are each independently a moiety of R⁴ asdescribed herein, including in embodiments. In embodiments, R^(4.1) isunsubstituted methoxy. In embodiments, R^(4.2) is unsubstituted methoxy.In embodiments, R^(4.3) is unsubstituted methoxy. In embodiments,R^(4.4) is unsubstituted methoxy. In embodiments, R^(4.5) isunsubstituted methoxy. In embodiments, R^(4.2), R^(4.3), R^(4.4), andR^(4.5) are hydrogen and R^(4.1) is unsubstituted methoxy. Inembodiments, R^(4.1), R^(4.3), R^(4.4), and R^(4.5) are hydrogen andR^(4.2) is unsubstituted methoxy. In embodiments, R^(4.2), R^(4.1),R^(4.4), and R^(4.5) are hydrogen and R^(4.3) is unsubstituted methoxy.In embodiments, R^(4.2,), R^(4.3), R^(4.1), and R^(4.5) are hydrogen andR^(4.4) is unsubstituted methoxy. In embodiments, R^(4.2), R^(4.3),R^(4.4), and R^(4.1) are hydrogen and R^(4.5) is unsubstituted methoxy.In embodiments, R^(4.1) is unsubstituted ethoxy. In embodiments, R^(4.2)is unsubstituted ethoxy. In embodiments, R^(4.3) is unsubstitutedethoxy. In embodiments, R^(4.4) is unsubstituted ethoxy. In embodiments,R^(4.5) is unsubstituted ethoxy. In embodiments, R^(4.2), R^(4.3),R^(4.4), and R^(4.5) are hydrogen and R^(4.1) is unsubstituted ethoxy.In embodiments, R^(4.1), R^(4.3), R^(4.4), and R^(4.5) are hydrogen andR^(4.2) is unsubstituted ethoxy. In embodiments, R^(4.2), R^(4.1),R^(4.4), and R^(4.5) are hydrogen and R^(4.3) is unsubstituted ethoxy.In embodiments, R^(4.2), R^(4.3), R^(4.1), and R^(4.5) are hydrogen andR^(4.4) is unsubstituted ethoxy. In embodiments, R^(4.2), R^(4.3),R^(4.4), and R^(4.1) are hydrogen and R^(4.5) is unsubstituted ethoxy.In embodiments, R^(4.1) is —OH. In embodiments R^(4.2) is —OH. Inembodiments, R^(4.3) is —OH. In embodiments, R^(4.4) is —OH. Inembodiments, R^(4.5) is —OH. In embodiments, R^(4.2), R^(4.3), R^(4.4),and R^(4.5) are hydrogen and R^(4.1) is —OH. In embodiments, R^(4.1),R^(4.3), R^(4.4), and R^(4.5) are hydrogen and R^(4.2) is —OH. Inembodiments, R^(4.2), R^(4.1), R^(4.4), and R^(4.5) are hydrogen andR^(4.3) is —OH. In embodiments, R^(4.2), R^(4.3), R^(4.1), and R^(4.5)are hydrogen and R^(4.4) is —OH. In embodiments, R^(4.2), R^(4.3),R^(4.4), and R^(4.1) are hydrogen and R^(4.5) is —OH. In embodiments,R^(4.1) is halogen. In embodiments, R^(4.2) is halogen. In embodiments,R^(4.3) is halogen. In embodiments, R^(4.4) is halogen. In embodiments,R^(4.5) is halogen. In embodiments, R^(4.2), R^(4.3), R^(4.4), andR^(4.5) are hydrogen and R^(4.1) is halogen. In embodiments, R^(4.1),R^(4.3), R^(4.4), and R^(4.5) are hydrogen and R^(4.2) is halogen. Inembodiments, R^(4.2), R^(4.1), R^(4.4), and R^(4.5) are hydrogen andR^(4.3) is halogen. In embodiments, R^(4.2), R^(4.3), R^(4.1), andR^(4.5) are hydrogen and R^(4.4) is halogen. In embodiments, R^(4.2),R^(4.3), R^(4.4), and R^(4.1) are hydrogen and R^(4.5) is halogen. Inembodiments, R^(4.1) is unsubstituted methyl. In embodiments, R^(4.2) isunsubstituted methyl. In embodiments, R^(4.3) is unsubstituted methyl.In embodiments, R^(4.4) is unsubstituted methyl. In embodiments, R^(4.5)is unsubstituted methyl. In embodiments, R^(4.2), R^(4.3), R^(4.4), andR^(4.5) are hydrogen and R^(4.1) is unsubstituted methyl. Inembodiments, R^(4.1), R^(4.3), R^(4.4), and R^(4.5) are hydrogen andR^(4.2) is unsubstituted methyl. In embodiments, R^(4.2), R^(4.1),R^(4.4), and R^(4.5) are hydrogen and R^(4.3) is unsubstituted methyl.In embodiments, R^(4.2), R^(4.3), R^(4.1), and R^(4.5) are hydrogen andR^(4.4) is unsubstituted methyl. In embodiments, R^(4.2), R^(4.3),R^(4.4), and R^(4.1) are hydrogen and R^(4.5) is unsubstituted methyl.In embodiments, one or more of R^(1.1), R^(1.2), R^(1.3), R^(1.4),R^(4.1), R^(4.2), R^(4.3), R^(4.4), R^(4.5), R² and/or R³ are hydrogen.It will be understood that R⁵ is/are a floating substituent and may bepositioned on either or both rings.

In embodiments, the compound has the formula:

R^(1.1), R^(1.3), R^(1.4), R², R³, R^(4.1), R^(4.3), R^(4.4), R^(4.5),R⁵, W¹, W², W³, and z3 are as described herein, including in compoundsof formula (I) to (XI). It will be understood that R⁵ is/are a floatingsubstituent and may be positioned on either or both rings. R^(1.1),R^(1.3), and R^(1.4) are each independently a moiety of R¹ as describedherein, including in embodiments. R^(4.1), R^(4.3), R^(4.4,) and R^(4.5)are each independently a moiety of R⁴ as described herein, including inembodiments. In embodiments, R^(1.1), R^(1.3), and/or R^(1.4) arehydrogen. In embodiments, R^(4.1), R^(4.2), R^(4.3), R^(4.4), and/orR^(4.5) are hydrogen. In embodiments, R² is hydrogen. In embodiments, R³is hydrogen. In embodiments R^(1.1) is halogen. In embodiments R^(1.3)is halogen. In embodiments R^(1.4) is halogen. In embodiments R^(1.1) s—Cl. In embodiments R^(1.3) is —Cl. In embodiments R^(1.4) is —Cl. Inembodiments R^(1.1) is —F. In embodiments R^(1.3) is —F. In embodimentsR^(1.4) is —F. In embodiments R^(1.3) and R^(1.4) are hydrogen andR^(1.1) is halogen. In embodiments R^(1.1) and R^(1.4) are hydrogen andR^(1.3) is halogen. In embodiments R^(1.3) and R^(1.1) are hydrogen andR^(1.4) is halogen. In embodiments R^(1.3) and R^(1.4) are hydrogen andR^(1.1) is —Cl. In embodiments R^(1.1) and R^(1.4) are hydrogen andR^(1.3) is —Cl. In embodiments R^(1.3) and R^(1.1) are hydrogen andR^(1.1) is —Cl. In embodiments R^(1.3) and R^(1.4) are hydrogen andR^(1.1) is —F. In embodiments R^(1.1) and R^(1.4) are hydrogen andR^(1.3) is —F. In embodiments R^(1.3) and R^(1.1) are hydrogen andR^(1.1) is —F. W¹ is N or C(R^(4.2)). W² is N or C(R^(5.1)). W³ is N orC(R^(5.2)). In embodiments, W¹ is N. In embodiments, W² is N. Inembodiments, W³ is N. In embodiments, W¹ is C(R^(4.2)). In embodiments,W² is C(R^(5.1)). In embodiments, W³ is C(R^(5.2)). In embodiments, W¹is CH. In embodiments, W² is CH. In embodiments, W³ is CH. R^(5.1) andR^(5.2) are each independently a moiety of R⁵ as described herein,including in embodiments. In embodiment, z3 is 0. R^(4.1), R^(4.2),R^(4.3), R^(4.4), and R^(4.5) are each independently a moiety of R⁴ asdescribed herein, including in embodiments. In embodiments, R^(4.1) isunsubstituted methoxy. In embodiments, R^(4.2) is unsubstituted methoxy.In embodiments, R⁴³ is unsubstituted methoxy. In embodiments, R^(4.4) isunsubstituted methoxy. In embodiments, R^(4.5) is unsubstituted methoxy.In embodiments, R^(4.2), R^(4.3), R^(4.4), and R^(4.5) are hydrogen andR^(4.1) is unsubstituted methoxy. In embodiments, R^(4.1), R^(4.3),R^(4.4), and R^(4.5) are hydrogen and R^(4.2) is unsubstituted methoxy.In embodiments, R^(4.2), R^(4.1), R^(4.4), and R^(4.5) are hydrogen andR^(4.3) is unsubstituted methoxy. In embodiments, R^(4.2), R^(4.3),R^(4.1), and R^(4.5) are hydrogen and R^(4.4) is unsubstituted methoxy.In embodiments, R^(4.2), R^(4.3), R^(4.4), and R^(4.1) are hydrogen andR^(4.5) is unsubstituted methoxy. In embodiments, R^(4.1) isunsubstituted ethoxy. In embodiments, R^(4.2) is unsubstituted ethoxy.In embodiments, R^(4.3) is unsubstituted ethoxy. In embodiments, R^(4.4)is unsubstituted ethoxy. In embodiments, R^(4.5) is unsubstitutedethoxy. In embodiments, R^(4.2), R^(4.3), R^(4.4), and R^(4.5) arehydrogen and R^(4.1) is unsubstituted ethoxy. In embodiments, R^(4.1),R^(4.3), R^(4.4), and R^(4.5) are hydrogen and R^(4.2) is unsubstitutedethoxy. In embodiments, R^(4.2), R^(4.1), R^(4.4), and R^(4.5) arehydrogen and R^(4.3) is unsubstituted ethoxy. In embodiments, R^(4.2),R^(4.3), R^(4.1) and R^(4.5) are hydrogen and R^(4.4) is unsubstitutedethoxy. In embodiments, R^(4.2), R^(4.3), R^(4.4) and R^(4.1) arehydrogen and R^(4.5) is unsubstituted ethoxy. In embodiments, R^(4.1) is—OH. In embodiments R^(4.2) is —OH. In embodiments, R^(4.3) is —OH. Inembodiments, R^(4.4) is —OH. In embodiments, R^(4.5) is —OH. Inembodiments, R^(4.2), , R^(4.3), R^(4.4,) and R^(4.5) are hydrogen andR^(4.1) is —OH. In embodiments, R^(4.1) _(, R) ^(4.3) _(, R) ^(4.4), andR^(4.5) are hydrogen and R^(4.2) is —OH. In embodiments, R^(4.2),R^(4.1), R^(4.4), and R^(4.5) are hydrogen and R^(4.3) is —OH. Inembodiments, R^(4.2), R^(4.3), R^(4.1), and R^(4.5) are hydrogen andR^(4.4) is —OH. In embodiments, R^(4.2), R^(4.3), R^(4.4), and R^(4.1)are hydrogen and R^(4.5) is —OH. In embodiments, R^(4.1) is halogen. Inembodiments, R^(4.2) is halogen. In embodiments, R^(4.3) is halogen. Inembodiments, R^(4.4) is halogen. In embodiments, R^(4.5) is halogen. Inembodiments, R^(4.2), R^(4.3), R^(4.4) and R^(4.5) are hydrogen andR^(4.1) is halogen. In embodiments, R^(4.1), R^(4.3), R^(4.4), andR^(4.5) are hydrogen and R^(4.2) is halogen. In embodiments, R^(4.2),R^(4.1), R^(4.4), and R^(4.5) are hydrogen and R^(4.3) is halogen. Inembodiments, R^(4.2), R^(4.3), R^(4.1), and R^(4.5) are hydrogen andR^(4.4) is halogen. In embodiments, R^(4.2), R^(4.3), R^(4.4), andR^(4.1) are hydrogen and R^(4.5) is halogen. In embodiments, R^(4.1) isunsubstituted methyl. In embodiments, R^(4.2) is unsubstituted methyl.In embodiments, R^(4.3) is unsubstituted methyl. In embodiments, R^(4.4)is unsubstituted methyl. In embodiments, R^(4.5) is unsubstitutedmethyl. In embodiments, R^(4.2), R^(4.3), R^(4.4), and R^(4.5) arehydrogen and R^(4.1) is unsubstituted methyl. In embodiments, R^(4.1),R^(4.3), R^(4.4), and R^(4.5) are hydrogen and R^(4.2) is unsubstitutedmethyl. In embodiments, R^(4.2), R^(4.1), R^(4.4 ,) and R^(4.5) arehydrogen and R^(4.3) is unsubstituted methyl. In embodiments, R^(4.2),R^(4.3), R^(4.1), and R^(4.5) are hydrogen and R^(4.4) is unsubstitutedmethyl. In embodiments, R^(4.2), R^(4.3), R^(4.4), and R^(4.1) arehydrogen and R^(4.5) is unsubstituted methyl. In embodiments, one ormore of R^(1.1), R^(1.3), R^(1.4), R^(4.1), R^(4.2), R^(4.3), R^(4.4),R^(4.5), R² and/or R³ are hydrogen. It will be understood that R⁵ is/area floating substituent and may be positioned on either or both rings.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments the compound has the formula:

Table 1. Examples of compounds of formula (I), (II), (III), (IV) and (V)are shown in the table below:

Compound ID Structures AOH1160

PCNA1

PCNA2

PCNA3

PCNA3A

PCNA4

PCNA6

PCNA7/AOH1996

#1161

#1162

#1165

#1166

#1167

#1175

#1176

#1177

#1178

AOH1179

AOH1180

In embodiments, the compound binds the interdomain connecting loop ofPCNA (e.g., the loop including the amino acids corresponding to humanPCNA M121 to Y133). In embodiments, the compound binds to an amino acidin the sequence corresponding to human PCNA M121 to Y133. Inembodiments, the compound binds an amino acid in the sequencecorresponding to human PCNA L126 to Y133. In embodiments, the compoundbinds to a plurality of amino acids in the sequence corresponding tohuman PCNA M121 to Y133. In embodiments, the compound binds a pluralityof amino acids in the sequence corresponding to human PCNA L126 to Y133.In embodiments, the compound binds to an amino acid in human PCNA M121to Y133. In embodiments, the compound binds an amino acid in human PCNAL126 to Y133. In embodiments, the compound binds to a plurality of aminoacids in human PCNA M121 to Y133. In embodiments, the compound binds aplurality of amino acids in human PCNA L126 to Y133. In embodiments, thecompound binds an amino acid corresponding to human PCNA L126. Inembodiments, the compound binds an amino acid corresponding to humanPCNA G127. In embodiments, the compound binds an amino acidcorresponding to human PCNA 1128. In embodiments, the compound binds anamino acid corresponding to human PCNA P129. In embodiments, thecompound binds an amino acid corresponding to human PCNA E130. Inembodiments, the compound binds an amino acid corresponding to humanPCNA Q131. In embodiments, the compound binds an amino acidcorresponding to human PCNA E132. In embodiments, the compound binds anamino acid corresponding to human PCNA Y133. In embodiments, thecompound binds an amino acid corresponding to human PCNA D41. Inembodiments, the compound binds an amino acid corresponding to humanPCNA S42. In embodiments, the compound binds an amino acid correspondingto human PCNA S43. In embodiments, the compound binds an amino acidcorresponding to human PCNA H44. In embodiments, the compound binds anamino acid corresponding to human PCNA V45. In embodiments, the compoundbinds an amino acid corresponding to human PCNA P234. In embodiments,the compound binds to human PCNA L126. In embodiments, the compoundbinds to human PCNA G127. In embodiments, the compound binds to humanPCNA 1128. In embodiments, the compound binds to human PCNA P129. Inembodiments, the compound binds to human PCNA E130. In embodiments, thecompound binds to human PCNA Q131. In embodiments, the compound binds tohuman PCNA E132. In embodiments, the compound binds to human PCNA Y133.In embodiments, the compound binds to human PCNA D41. In embodiments,the compound binds to human PCNA S42. In embodiments, the compound bindsto human PCNA S43. In embodiments, the compound binds to human PCNA H44.In embodiments, the compound binds to human PCNA V45. In embodiments,the compound binds to human PCNA P234. In embodiments, the compoundcompetes with T3 for binding to PCNA. In embodiments, the compoundcompetes with p21 (CDKN1A) for binding to PCNA. In embodiments, thecompound competes with DNA polymerase 6 for binding to PCNA. Inembodiments, the compound competes with flap endonuclease 1 (FEN1) forbinding to PCNA. In embodiments, the compound inhibits T3 binding toPCNA. In embodiments, the compound inhibits p21 (CDKN1A) binding toPCNA. In embodiments, the compound inhibits DNA polymerase δ binding toPCNA. In embodiments, the compound inhibits flap endonuclease 1 (FEN1)binding to PCNA. In embodiments, the compound inhibits PIP-boxcontaining protein (e.g., PIP box includes eight amino acid sequence ofQXX-(hydrophobic amino acid)-XX-(acidic amino acid)-(acidic amino acid),X is independently any amino acid) binding to PCNA. In embodiments, thecompound inhibits DNA replication. In embodiments, the compound reducesDNA replication (e.g., relative to the absence of the compound, orrelative to control). In embodiments, the compound inhibits DNA repair.In embodiments, the compound reduces DNA repair (e.g., relative to theabsence of the compound, or relative to control). In embodiments, thecompound inhibits cell (e.g., cancer cell) growth. In embodiments, thecompound reduces cell (e.g., cancer cell) growth (e.g., relative to theabsence of the compound, or relative to control). In embodiments, thecompound inhibits cell (e.g., cancer cell) proliferation. Inembodiments, the compound reduces cell (e.g., cancer cell) proliferation(e.g., relative to the absence of the compound, or relative to control).In embodiments, the compound inhibits cell survival. In embodiments, thecompound reduces cell survival (e.g., relative to the absence of thecompound, or relative to control). In embodiments, the compound bindsthe acidic form of PCNA (e.g., caPCNA, form having an acidic isoelectricpoint). In embodiments, the compound does not bind the basic form ofPCNA (e.g., nmPCNA, form having an apparent basic isoelectric point). Inembodiments, the compound binds the acidic form of PCNA (e.g., caPCNA,form having an acidic isoelectric point) more strongly than the basicform of PCNA (e.g., nmPCNA, form having an apparent basic isoelectricpoint) (e.g., about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3,4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300,400, 500, 600, 700, 800, 900, 1000, 10000, or 100000-fold). Inembodiments, the compound inhibits homologous recombination. Inembodiments, the compound reduces homologous recombination (e.g.,relative to the absence of the compound or relative to control). Inembodiments, the compound induces cell cycle arrest. In embodiments, thecompound increases cell cycle arrest. In embodiments, the compound slowstumor growth. In embodiments, the compound reduces tumor growth. Inembodiments, the compound induces apoptosis. In embodiments, thecompound induces apoptosis of cancer cells. In embodiments, the compoundinduces apoptosis of cancer cells to a greater degree than healthy cellsof the same cell type (e.g., about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90,100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 10000, or 100000-foldmore). In embodiments, the compound induces apoptosis of cancer cells toa greater degree than healthy cells of the same cell type (e.g., 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20,30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900,1000, 10000, or 100000-fold more). In embodiments, the compound inducescell death of cancer cells at a lower compound concentration than forhealthy cells (e.g., at an IC50 at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100,200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000,6000, 7000, 8000, 9000, or 10000-fold lower). In embodiments, thecompound increases S phase arrest. In embodiments, the compoundincreases G2 phase arrest. In embodiments, the compound increases thelevel of double strand breaks. In embodiments, the compound inhibits DNArepair (e.g., relative to the absence of the compound or relative tocontrol). In embodiments, the compound does not reduce non-homologousend joining. In embodiments, the compound does not inhibitnon-homologous end joining. In embodiments, the compound does notactivate thyroid receptor. In embodiments, the compound increasescaspase-3 activity. In embodiments, the compound increases caspase-9activity.

In embodiments, the compound binds to a PCNA protein that ispost-translationally modified with a stronger affinity than to the samePCNA protein that is not post-translationally modified. In embodiments,the compound binds to a PCNA protein that is not post-translationallymodified with a stronger affinity than to the same PCNA protein that ispost-translationally modified. In embodiments, the compound binds with astronger affinity to a PCNA protein that is post-translationallymodified with a lipid than to the same PCNA protein that is notpost-translationally modified with the lipid. In embodiments, thecompound binds with a stronger affinity to a PCNA protein that is notpost-translationally modified with a lipid than to the same PCNA proteinthat is post-translationally modified with the lipid. In embodiments,the compound binds with a stronger affinity to a PCNA protein that ispost-translationally modified with a sugar than to the same PCNA proteinthat is not post-translationally modified with the sugar. Inembodiments, the compound binds with a stronger affinity to a PCNAprotein that is not post-translationally modified with a sugar than tothe same PCNA protein that is post-translationally modified with thesugar. In embodiments, the compound binds with a stronger affinity to aPCNA protein that is post-translationally modified with an amino acidthan to the same PCNA protein that is not post-translationally modifiedwith the amino acid. In embodiments, the compound binds with a strongeraffinity to a PCNA protein that is not post-translationally modifiedwith an amino acid than to the same PCNA protein that ispost-translationally modified with the amino acid. In embodiments, thecompound binds with a stronger affinity to a PCNA protein that ispost-translationally modified with a nucleobase than to the same PCNAprotein that is not post-translationally modified with the nucleobase.In embodiments, the compound binds with a stronger affinity to a PCNAprotein that is not post-translationally modified with a nucleobase thanto the same PCNA protein that is post-translationally modified with thenucleobase. In embodiments, the compound binds with a stronger affinityto a PCNA protein that is post-translationally modified with a phosphatethan to the same PCNA protein that is not post-translationally modifiedwith the phosphate. In embodiments, the compound binds with a strongeraffinity to a PCNA protein that is not post-translationally modifiedwith a phosphate than to the same PCNA protein that ispost-translationally modified with the phosphate. In embodiments, thecompound binds with a stronger affinity to a PCNA protein that ispost-translationally modified with a acetyl than to the same PCNAprotein that is not post-translationally modified with the acetyl. Inembodiments, the compound binds with a stronger affinity to a PCNAprotein that is not post-translationally modified with a acetyl than tothe same PCNA protein that is post-translationally modified with theacetyl. In embodiments, the compound binds with a stronger affinity to aPCNA protein that is phosphorylated than to the same PCNA protein thatis not phosphorylated. In embodiments, the compound binds with astronger affinity to a PCNA protein that is not phosphorylated than tothe same PCNA protein that is phosphorylated. In embodiments, thecompound binds with a stronger affinity to a PCNA protein that isalkylated (e.g., methylated) than to the same PCNA protein that is notalkylated (e.g., methylated). In embodiments, the compound binds with astronger affinity to a PCNA protein that is not alkylated (e.g.,methylated) than to the same PCNA protein that is alkylated (e.g.,methylated). In embodiments, the compound binds with a stronger affinityto a PCNA protein that is ribosylated than to the same PCNA protein thatis not ribosylated. In embodiments, the compound binds with a strongeraffinity to a PCNA protein that is not ribosylated than to the same PCNAprotein that is ribosylated. In embodiments, the compound binds with astronger affinity to a PCNA protein that is acetylated than to the samePCNA protein that is not acetylated. In embodiments, the compound bindswith a stronger affinity to a PCNA protein that is not acetylated thanto the same PCNA protein that is acetylated. In embodiments, thecompound binds with a stronger affinity to a PCNA protein that isglycosylated than to the same PCNA protein that is not glycosylated. Inembodiments, the compound binds with a stronger affinity to a PCNAprotein that is not glycosylated than to the same PCNA protein that isglycosylated. In embodiments, the compound binds with a strongeraffinity to a PCNA protein that is lipidated than to the same PCNAprotein that is not lipidated. In embodiments, the compound binds with astronger affinity to a PCNA protein that is not lipidated than to thesame PCNA protein that is lipidated. In embodiments, the compound bindswith a stronger affinity to a PCNA protein that is poly(ADP) ribosylatedthan to the same PCNA protein that is not poly(ADP) ribosylated. Inembodiments, the compound binds with a stronger affinity to a PCNAprotein that is not poly(ADP) ribosylated than to the same PCNA proteinthat is poly(ADP) ribosylated. In embodiments, the compound binds with astronger affinity to a PCNA protein that is post-translationallymodified with a methylester of an acidic amino acid than to the samePCNA protein that is not post-translationally modified with themethylester of an acidic amino acid. In embodiments, the compound bindswith a stronger affinity to a PCNA protein that is notpost-translationally modified with a methylester of an acidic amino acidthan to the same PCNA protein that is post-translationally modified withthe methylester of an acidic amino acid. In embodiments, thepost-translational modification is on an amino acid in the sequencecorresponding to human PCNA M121 to Y133. In embodiments, thepost-translational modification is on an amino acid in the sequencecorresponding to human PCNA L126 to Y133. In embodiments, an increase ordecrease (e.g., in binding or activity or level of protein or function,as described herein above) associated with a compound described herein,is in comparison to a control (e.g., identical experiment or conditionsexcept for the absence of the compound described herein).

In embodiments, the compound (e.g., described herein) has a half-life ofat least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160,170, 180, 190, 200, 210, 20, 230, 240, 250, 260, 270, 280, 290, 300,310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440,450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580,590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720,730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860,870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000hours. In embodiments, the compound (e.g., described herein) has ahalf-life of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140,150, 160, 170, 180, 190, 200, 210, 20, 230, 240, 250, 260, 270, 280,290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420,430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560,570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700,710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840,850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980,990, or 1000 hours. In embodiments, the compound (e.g., describedherein) has a half-life of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 2, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120,130, 140, 150, 160, 170, 180, 190, 200, 210, 20, 230, 240, 250, 260,270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400,410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540,550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680,690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820,830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960,970, 980, 990, or 1000 hours. In embodiments, the half-life is a plasmahalf-life. In embodiments, the half-life is a tissue half-life. Inembodiments, the half-life is the half-life in a cell. In embodiments,the half-life is a blood half-life.

In embodiments, a compound is a compound described herein, including inan aspect, embodiment, table, figure, example, scheme, or claim.

C. PHARMACEUTICAL COMPOSITIONS

In another aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound, orpharmaceutically acceptable salt thereof, as described herein, includingembodiments.

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient (e.g., compound describedherein) is contained in a therapeutically effective amount, i.e., in anamount effective to achieve its intended purpose. The actual amounteffective for a particular application will depend, inter alia, on thecondition being treated. When administered in methods to treat adisease, such compositions will contain an amount of active ingredienteffective to achieve the desired result, e.g., inhibiting cellproliferation. Determination of a therapeutically effective amount of acompound of the invention is well within the capabilities of thoseskilled in the art, especially in light of the detailed disclosureherein. In embodiments, the pharmaceutical composition may include asecond agent. In embodiments, the second agent is an anti-cancer agent.In embodiments, the second agent is a chemotherapeutic agent. Inembodiments, the second agent is included in a therapeutically effectiveamount. In embodiments, the second agent is an agent for treating braincancer. In embodiments, the second agent is an agent for treatingneuroblastoma. In embodiments, the second agent is an agent for treatingglioblastoma. In embodiments, the second agent is an agent for treatinga central nervous system (CNS) cancer. In embodiments, the second agentis an agent for treating a sympathetic nervous system (SNS) cancer. Inembodiments, the second agent is an agent for treating an adrenal glandcancer. In embodiments, the second agent is an agent for treating acancer of a neuron in the neck, chest, abdomen, or pelvis. Inembodiments, the second agent is an agent for treatingesthesioneuroblastoma. In embodiments, the second agent includes stemcells (e.g., bone marrow or hematopietic stem cells). In embodiments,the second agent is 13-cis-retinoic acid. In embodiments, the secondagent is GM-CSF. In embodiments, the second agent is IL-2. Inembodiments, the second agent is a platinum-based compound (e.g.,anti-cancer agent). In embodiments, the second agent is cisplatin. Inembodiments, the second agent is carboplatin. In embodiments, the secondagent is oxaloplatin.

In embodiments, the second agent is a DNA damaging agent or cytotoxicagent in routine clinical use for treating cancer.In embodiments, thesecond agent is an alkylating agent. In embodiments, the second agent iscyclophosphamide. In embodiments, the second agent is ifosfamide. Inembodiments, the second agent is melphalan. In embodiments, the secondagent is topoisomerase II inhibitor. In embodiments, the second agent isetoposide. In embodiments, the second agent is an anthracyclineantibiotic. In embodiments, the second agent is doxorubicin. Inembodiments, the second agent is a vinca alkaloid. In embodiments, thesecond agent is vincristine. In embodiments, the second agent istopotecan. In embodiments, the second agent is irinotecan.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid in a mixture with thefinely divided active component (e.g. a compound provided herein). Intablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom 5% to 70% of the active compound.

Suitable solid excipients include, but are not limited to, magnesiumcarbonate; magnesium stearate; talc; pectin; dextrin; starch;tragacanth; a low melting wax; cocoa butter; carbohydrates; sugarsincluding, but not limited to, lactose, sucrose, mannitol, or sorbitol,starch from corn, wheat, rice, potato, or other plants; cellulose suchas methyl cellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins including, but not limited to, gelatin and collagen. Ifdesired, disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragees cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

When parenteral application is needed or desired, particularly suitableadmixtures for the compounds of the invention are injectable, sterilesolutions, preferably oily or aqueous solutions, as well as suspensions,emulsions, or implants, including suppositories. In particular, carriersfor parenteral administration include aqueous solutions of dextrose,saline, pure water, ethanol, glycerol, propylene glycol, peanut oil,sesame oil, polyoxyethylene-block polymers, and the like. Ampules areconvenient unit dosages. The compounds of the invention can also beincorporated into liposomes or administered via transdermal pumps orpatches. Pharmaceutical admixtures suitable for use in the presentinvention are well-known to those of skill in the art and are described,for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co.,Easton, Pa.) and WO 96/05309, the teachings of both of which are herebyincorporated by reference.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component (e.g. compounds described herein, includingembodiments, examples, compounds of Table 1) in water and addingsuitable colorants, flavors, stabilizers, and thickening agents asdesired. Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, anddispersing or wetting agents such as a naturally occurring phosphatide(e.g., lecithin), a condensation product of an alkylene oxide with afatty acid (e.g., polyoxyethylene stearate), a condensation product ofethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethylene oxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol (e.g.,polyoxyethylene sorbitol mono-oleate), or a condensation product ofethylene oxide with a partial ester derived from fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can contain a thickening agent, such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents can be added to provide apalatable oral preparation, such as glycerol, sorbitol or sucrose. Theseformulations can be preserved by the addition of an antioxidant such asascorbic acid. As an example of an injectable oil vehicle, see Minto, J.Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulationsof the invention can also be in the form of oil-in-water emulsions. Theoily phase can be a vegetable oil or a mineral oil, described above, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion can also contain sweetening agents and flavoring agents, as inthe formulation of syrups and elixirs. Such formulations can alsocontain a demulcent, a preservative, or a coloring agent.

The compounds of the invention can be administered alone or can becoadministered to the patient. Coadministration is meant to includesimultaneous or sequential administration of the compounds individuallyor in combination (more than one compound). Thus, the preparations canalso be combined, when desired, with other active substances (e.g. toreduce metabolic degradation).

In embodiments, the pharmaceutical composition further includes ananti-cancer agent. In embodiments, the anti-cancer agent is aplatinum-based compound. In embodiments, the anti-cancer agent iscisplatin. In embodiments, the anti-cancer agent is oxaloplatin. Inembodiments, the anti-cancer agent is carboplatin. In embodiments, thepharmaceutical composition includes a compound as described herein and asecond agent, for example an anti-cancer agent (e.g., cisplatin,oxaloplatin, or carboplatin). In embodiments, the pharmaceuticalcomposition further includes 13-cis-retinoid acid.

The compounds of the present invention can be prepared and administeredin a wide variety of oral, parenteral and topical dosage forms. Oralpreparations include tablets, pills, powder, dragees, capsules, liquids,lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitablefor ingestion by the patient. The compounds of the present invention canalso be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. Also, the compounds described herein can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the present invention can be administered transdermally. Itis also envisioned that multiple routes of administration (e.g.,intramuscular, oral, transdermal) can be used to administer thecompounds of the invention. Accordingly, the present invention alsoprovides pharmaceutical compositions comprising a pharmaceuticallyacceptable excipient and one or more compounds of the invention.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The quantity ofactive compound may also be defined as mg/kg, ranging from about 0.1mg/kg to 500 mg/kg. For example, the active compound can be administeredin an amount of 30 mg/kg. The composition can, if desired, also containother compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60 and 80; Pluronic F-68, F-84and P-103; cyclodextrin; polyoxyl 35 castor oil; or other agents knownto those skilled in the art. Such co-solvents are typically employed ata level between about 0.01% and about 2% by weight.

Viscosity greater than that of simple aqueous solutions may be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, combinations of the foregoing, and other agents known tothose skilled in the art. Such agents are typically employed at a levelbetween about 0.01% and about 2% by weight. Determination of acceptableamounts of any of the above adjuvants is readily ascertained by oneskilled in the art.

The ratio between toxicity and therapeutic effect for a particularcompound is its therapeutic index and can be expressed as the ratiobetween LD₅₀ (the amount of compound lethal in 50% of the population)and ED₅₀ (the amount of compound effective in 50% of the population).Compounds that exhibit high therapeutic indices are preferred.Therapeutic index data obtained from cell culture assays and/or animalstudies can be used in formulating a range of dosages for use in humans.The dosage of such compounds preferably lies within a range of plasmaconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. See, e.g. Fingl etal., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch.1, p.1, 1975. Theexact formulation, route of administration and dosage can be chosen bythe individual physician in view of the patient's condition and theparticular method in which the compound is used.

D. METHODS OF TREATMENT

In an aspect is provided, a method of treating cancer, wherein themethod includes administering a compound described herein to a subjectin need thereof. In embodiments, the method includes administering atherapeutically effective amount of the compound. In embodiments, thecancer is associated with an increased level of caPCNA compared to acontrol (e.g., non-malignant cells). In embodiments, the cancer includescancer cells. In embodiments, the cancer cells are associated with anincreased level of caPCNA compared to a control (e.g., non-malignantcells). In embodiments, the ratio of caPCNA:nmPCNA is increased comparedto a control. In embodiments, the cancer expresses caPCNA. Inembodiments, the cancer expresses an increased level caPCNA as comparedto a control (e.g., benign cells).

In embodiments, the cancer cells associated with an increased level ofcaPCNA is cervical cancer, colon cancer, thyroid cancer, gastric cancer,ovarian cancer, breast cancer, lung cancer, uterine cancer, or Ductalcarcinoma in situ (DCIS).

The compounds described herein are useful, inter alfa, in methods oftreating cancer. Such methods include administering to a subject in needthereof an effective amount of a compound described herein, includingembodiments and pharmaceutically acceptable salts thereof. Inembodiments, the compound is chosen from a table disclosed herein (e.g.,Table 1, Table 3). In embodiments, the compound is chosen from Table 1.In embodiments, the compound is chosen from Table 3.

In embodiments, the cancer is neuroblastoma. In embodiments, the canceris metastatic cancer. In embodiments, the cancer is breast cancer. Inembodiments, the cancer is triple negative breast cancer. Inembodiments, the cancer is metastatic breast cancer. In embodiments, thecancer is brain cancer. In embodiments, the cancer is glioblastoma. Inembodiments, the cancer is astrocytoma. In embodiments, the cancer isglioma. In embodiments, the cancer is pancreatic cancer. In embodiments,the cancer is lympohoma. In embodiments, the cancer is chronic lymphoidleukemia (CLL). In embodiments, the cancer is non-Hodgkin's lymphoma. Inembodiments, the cancer is skin cancer. In embodiments, the cancer issquamous cell carcinoma. In embodiments, the cancer is T lymphotrophicleukemia. In embodiments, the cancer is melanoma. In embodiments, thecancer is malignant melanoma. In embodiments, the cancer is lung cancer.In embodiments, the cancer is non-small cell lung cancer. Inembodiments, the cancer is colon cancer. In embodiments, the cancer isprostate cancer. In embodiments, the cancer is ovarian cancer. Inembodiments, the cancer is leukemia. In embodiments, the cancer iskidney cancer. In embodiments, the cancer may be prostate, thyroid,endocrine system, brain, breast, cervix, colon, head & neck, liver,kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary,sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreaticcancer. Additional examples may include, but are not limited toHodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer,neuroblstoma, rhabdomyosarcoma, primary thrombocytosis, primarymacroglobulinemia, primary brain tumors, cancer, malignant pancreaticinsulanoma, malignant carcinoid, urinary bladder cancer, premalignantskin lesions, testicular cancer, lymphomas, thyroid cancer,neuroblastoma, esophageal cancer, genitourinary tract cancer, malignanthypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms ofthe endocrine or exocrine pancreas, medullary thyroid cancer, medullarythyroid carcinoma, melanoma, colorectal cancer, papillary thyroidcancer, hepatocellular carcinoma, or prostate cancer. In embodiments,the cancer is leukemia, myeloma, non-small cell lung cancer, coloncancer, central nervous system cancer, melanoma, ovarian cancer, renalcancer, prostate cancer, or breast cancer. In embodiments, the cancer istriple negative breast cancer. In embodiments, the cancer is a centralnervous system (CNS) cancer. In embodiments, the cancer is a sympatheticnervous system (SNS) cancer. In embodiments, the cancer is an adrenalgland cancer. In embodiments, the cancer is a cancer of a neuron in theneck, chest, abdomen, or pelvis. In embodiments, the cancer is anesthesioneuroblastoma. In embodiments, the cancer is a stage 1neuroblastoma (e.g., localized tumor confined to an area near theorigin). In embodiments, the cancer is a a stage 2A neuroblastoma (e.g.,Unilateral tumor with incomplete gross resection and/or identifiableipsilateral and contralateral lymph node negative for tumor). Inembodiments, the cancer is a a stage 2B neuroblastoma (e.g., Unilateraltumor with complete or incomplete gross resection;

with ipsilateral lymph node positive for tumor; identifiablecontralateral lymph node negative for tumor). In embodiments, the canceris a a stage 3 neuroblastoma (e.g., Tumor infiltrating across midlinewith or without regional lymph node involvement; or unilateral tumorwith contralateral lymph node involvement; or midline tumor withbilateral lymph node involvement). In embodiments, the cancer is a astage 4 neuroblastoma (e.g., Dissemination of tumor to distant lymphnodes, bone marrow, bone, liver, or other organs except as defined byStage 4S). In embodiments, the cancer is a a stage 4S neuroblastoma(e.g., Age <1 year old with localized primary tumor as described inStage 1 or Stage 2 above, with dissemination limited to liver, skin, orbone marrow (less than 10 percent of nucleated bone marrow cells aretumors). In embodiments, the cancer is a stage Ll neuroblastoma (e.g.,localized cancer without image-defined risk factors) according to theInternational Neuroblastoma Risk Group (INRG) staging system. Inembodiments, the cancer is a stage L2 neuroblastoma (e.g., localizedcancer with image-defined risk factors) according to the InternationalNeuroblastoma Risk Group (INRG) staging system. In embodiments, thecancer is a stage M neuroblastoma (e.g., metastatic cancer) according tothe International Neuroblastoma Risk Group (INRG) staging system. Inembodiments, the cancer is a stage MS neuroblastoma (e.g., metastaticcancer “special” where MS is equivalent to stage 4S as described above)according to the International Neuroblastoma Risk Group (INRG) stagingsystem. In embodiments, the cancer is a neuroblastoma riskstratification pre-treatment group, according to the InternationalNeuroblastoma Risk Group (INRG) staging system, of very low. Inembodiments, the cancer is a neuroblastoma risk stratificationpre-treatment group, according to the International Neuroblastoma RiskGroup (INRG) staging system, of low. In embodiments, the cancer is aneuroblastoma risk stratification pre-treatment group, according to theInternational Neuroblastoma Risk Group (INRG) staging system, ofintermediate. In embodiments, the cancer is a neuroblastoma riskstratification pre-treatment group, according to the InternationalNeuroblastoma Risk Group (INRG) staging system, of high risk.

In embodiments, the cancer is cervical cancer, colon cancer, thyroidcancer, gastric cancer, ovarian cancer, breast cancer, lung cancer,uterine cancer, or Ductal carcinoma in situ (DCIS). In embodiments, thecancer is cervical cancer. In embodiments, the cancer is colon cancer.In embodiments, the cancer is thyroid cancer. In embodiments, the canceris gastric cancer. In embodiments, the cancer is ovarian cancer. Inembodiments, the cancer is breast cancer. In embodiments, the cancer islung cancer. In embodiments, the cancer is uterine cancer. Inembodiments, the cancer is Ductal carcinoma in situ (DCIS).

In embodiments, the cancer is esophageal adenocarcinoma. In embodiments,the cancer is stage 0 esophageal cancer. In embodiments, the cancer isstage I esophageal cancer. In embodiments, the cancer is stage IAesophageal cancer. In embodiments, the cancer is stage D3 esophagealcancer. In embodiments, the cancer is stage IIA esophageal cancer. Inembodiments, the cancer is stage IIB esophageal cancer. In embodiments,the cancer is stage IIIA esophageal cancer. In embodiments, the canceris stage IIIB esophageal cancer. In embodiments, the cancer is stageIIIC esophageal cancer. In embodiments, the cancer is stage IVesophageal cancer. In embodiments, the cancer is stage I esophagealadenocarcinoma. In embodiments, the cancer is colorectal cancer. Inembodiments, the cancer is prostate cancer (e.g., prostaticadenocarcinoma). In embodiments, the cancer is high-grade prostaticintraepithelial neoplasia (PIN). In embodiments, the cancer isassociated with Barrett's esophagus. In embodiments, the cancer isassociated with Barrett's esophagus without epithelial dysplasia. Inembodiments, the cancer is associated with Barrett's esophagus with lowgrade epithelial dysplasia. In embodiments, the cancer is associatedwith Barrett's esophagus with high-grade epithelial dysplasia. Inembodiments, the cancer is oesophagogastric junctional adenocarcinoma.In embodiments, the cancer is described in Hammoud et al (Z. T. Hammoud,et al. Journal of Thoracic & Cardiovascular Surgery 2006;133(1):82-87);Wang X., et al. Prostate. 2011 May 15; 71(7):748-54; or Shen F., et al.J Cell Biochem. 2011 March; 112(3):756-60, which are incorporated byreference in their entirety for all purposes.

In embodiments, the compounds described herein are useful for methods oftreating neuroblastoma. In embodiments, the compounds described hereinare useful for methods of treating leukemia, non-small cell lung cancer,colon cancer, central nervous system cancer, melanoma, ovarian cancer,renal cancer, prostate cancer, or breast cancer.

Compounds described herein also inhibit cell proliferation inneuroblastoma cancer (e.g., cancer characterized by the cell lineBE(2)-C, SK-N-BE(2), SK-N—SH, SH-SYSY, IMR-32, SK-N-AS, SK-N-MC, MC-IXC,SHP-77, SK-N-FI, SK-N-DZ, CHP-212, BE(2)-M17, SK-N-FI, K-PN-DW, LA-N-2,LA-N-1, or LANS). Compounds described herein also inhibit cellproliferation in neuroblastoma cancer cell lines. For example, theseneuroblastoma cancer cell lines include BE(2)-C, SK-N-BE(2), SK-N—SH,SH-SYSY, IMR-32, SK-N-AS, SK-N-MC, MC-IXC, SHP-77, SK-N-FI, SK-N-DZ,CHP-212, BE(2)-M17, SK-N-FI, K-PN-DW, LA-N-2, LA-N-1, and LANS.

In embodiments, the cancer is a cancer identified in Table 6. Compoundsdescribed herein also inhibit cell proliferation in breast cancer (e.g.,cancer characterized by the cell line BT-549, HS 578T, MCF7,MDA-MB-231/ATCC, MDA-MB-468, or T-47D). Compounds described herein alsoinhibit cell proliferation in central nervous system cancer (e.g.,cancer characterized by the cell line SF-268, SF-295, SF-539, SNB-19,SNB-75, or U251). Compounds described herein also inhibit cellproliferation in colon cancer (e.g., cancer characterized by the cellline COLO 208, HCC-2998, HCT-116, HCT-15, HT29, KM12, or SW-620).Compounds described herein also inhibit cell proliferation in leukemiaor myeloma (e.g., cancer characterized by the cell line CCRF-CEM,HL-60(TB), K-562, MOLT-4, RPMI-8226, or SR). Compounds described hereinalso inhibit cell proliferation in melanoma (e.g., cancer characterizedby the cell line the LOX IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-2,SK-MEL-28, SK-MEL-5, UACC-257, or UACC-62). Compounds described hereinalso inhibit cell proliferation in Non-Small Cell Lung cancer (e.g.,cancer characterized by the cell line A549/ATCC, EKVX, HOP-62, HOP-92,NCI-H226, NCI-H23, NCI-H322M, NCI-H460, or NCI-H522). Compoundsdescribed herein also inhibit cell proliferation in ovarian cancer(e.g., cancer characterized by the cell line IGROV1, NCI/ADR-RES,OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, or SK-OV-3). Compounds describedherein also inhibit cell proliferation in prostate cancer (e.g., cancercharacterized by the cell line DU-145 or PC-3). Compounds describedherein also inhibit cell proliferation in renal cancer (e.g., cancercharacterized by the cell line 786-0, A498, ACHN, CAKI-1, RXF 393,SN12C, TK-10, or UO-31).

In embodiments, the cancer is a cancer identified in Table 6. Compoundsdescribed herein also inhibit cell proliferation in breast cancer celllines. For example, these breast cancer cell lines include BT-549, HS578T, MCF7, MDA-MB-231/ATCC, MDA-MB-468, and T-47D. Compounds describedherein also inhibit cell proliferation in central nervous system cancercell lines. For example, these central nervous system cancer cell linesinclude SF-268, SF-295, SF-539, SNB-19, SNB-75, and U251. Compoundsdescribed herein also inhibit cell proliferation in colon cancer celllines. For example, these colon cancer cell lines include COLO 208,HCC-2998, HCT-116, HCT-15, HT29, KM12, and SW-620. Compounds describedherein also inhibit cell proliferation in leukemia or myeloma celllines. For example, these leukemia or myeloma cell lines includeCCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226, and SR. Compoundsdescribed herein also inhibit cell proliferation in melanoma cell lines.For example, these melanoma cell lines include LOX IMVI, MALME-3M, M14,MDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, and UACC-62.Compounds described herein also inhibit cell proliferation in Non-SmallCell Lung cancer cell lines. For example, these Non-Small Cell Lungcancer cell lines include A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226,NCI-H23, NCI-H322M, NCI-H460, and NCI-H522. Compounds described hereinalso inhibit cell proliferation in ovarian cancer cell lines. Forexample, these ovarian cancer cell lines include IGROV1, NCI/ADR-RES,OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3. Compounds describedherein also inhibit cell proliferation in prostate cancer cell lines.For example, these prostate cancer cell lines include DU-145 and PC-3.Compounds described herein also inhibit cell proliferation in renalcancer cell lines. For example, these renal cancer cell lines include786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, and UO-31.

In another aspect a compound described herein is provided, includingembodiments (e.g. compound of formula (I), (II), (III), (IV), or (V), orany embodiment thereof; or in an example, table, figure, or claim), foruse as a medicament.

In another aspect is provided, a method of treating a disease associatedwith PCNA activity, wherein the method includes administering a compounddescribed herein to a subject in need thereof. In embodiments, themethod includes administering a therapeutically effective amount of thecompound. In embodiments the disease is Barrett's esophagus.

In embodiments, the method includes administering a second agent (e.g.,therapeutic agent). In embodiments, the second agent is an anti-canceragent. In embodiments, the anti-cancer agent is a platinum-basedcompound. In embodiments, the anti-cancer agent is cisplatin. Inembodiments, the anti-cancer agent is oxaloplatin. In embodiments, theanti-cancer agent is carboplatin. In embodiments, the anti-cancer agentis a DNA damaging agent or cytotoxic agent in routine clinical use fortreating cancer. In embodiments, the method includes administration ofhigh-dose chemotherapy. In embodiments, the method includes stem celltransplantation (HDCT/autoSCT). In embodiments, the method includesadministration of 13-cis-retinoid acid. In embodiments, the methodincludes administration of immunotherapy. In embodiments, the methodincludes administration of radiation. In embodiments, the second agentis a chemotherapeutic agent. In embodiments, the second agent isincluded in a therapeutically effective amount. In embodiments, thesecond agent is an agent for treating brain cancer. In embodiments, thesecond agent is an agent for treating neuroblastoma. In embodiments, thesecond agent is an agent for treating glioblastoma. In embodiments, thesecond agent is an agent for treating a central nervous system (CNS)cancer. In embodiments, the second agent is an agent for treating asympathetic nervous system (SNS) cancer. In embodiments, the secondagent is an agent for treating an adrenal gland cancer. In embodiments,the second agent is an agent for treating a cancer of a neuron in theneck, chest, abdomen, or pelvis. In embodiments, the second agent is anagent for treating esthesioneuroblastoma. In embodiments, the secondagent includes stem cells (e.g., bone marrow or hematopietic stemcells). In embodiments, the second agent is 13-cis-retinoic acid. Inembodiments, the second agent is GM-CSF. In embodiments, the secondagent is IL-2. In embodiments, the second agent is a platinum-basedcompound (e.g., anti-cancer agent). In embodiments, the second agent iscisplatin. In embodiments, the second agent is carboplatin. Inembodiments, the second agent is oxaloplatin. In embodiments, the secondagent is a DNA damaging agent or cytotoxic agent in routine clinical usefor treating cancer.In embodiments, the second agent is an alkylatingagent. In embodiments, the second agent is cyclophosphamide. Inembodiments, the second agent is ifosfamide. In embodiments, the secondagent is melphalan. In embodiments, the second agent is topoisomerase IIinhibitor. In embodiments, the second agent is etoposide. Inembodiments, the second agent is an anthracycline antibiotic. Inembodiments, the second agent is doxorubicin. In embodiments, the secondagent is a vinca alkaloid. In embodiments, the second agent isvincristine. In embodiments, the second agent is topotecan. Inembodiments, the second agent is irinotecan.

In embodiments, the disease is cancer (e.g., a cancer described herein,including neuroblastoma). In embodiments, the disease is systemic lupuserythematosus (SLE). In embodiments, the disease is mycosis fungoides.

E. METHODS OF INHIBITING PCNA

In another aspect is provided, a method of inhibiting PCNA activity,wherein the method includes contacting PCNA with an effective amount ofa compound described herein. In embodiments contacting includes allowinga compound described herein to interact with a protein of SEQ ID NO:2.In embodiments contacting includes allowing a compound described hereinto interact with a protein of SEQ ID NO:3. In embodiments contactingincludes allowing a compound described herein to interact with a proteinof SEQ ID NO:4.

The compounds described herein are useful, inter alfa, in methods ofinhibiting PCNA activity in a subject in need thereof, includingadministering to the subject an effective amount of a compound asdescribed herein, or a pharmaceutically acceptable salt thereof.

In embodiments, the PCNA is a human PCNA.

In embodiments, modulation of PCNA activity results in modulation of DNAreplication, DNA repair, and the cell cycle. For example, inhibition ofPCNA function induces cell cycle arrest resulting in apoptosis of cancercells, i.e. neuroblastoma cells.

In another aspect, compounds described herein are useful, inter alfa, ina method of treating a disease associated with PCNA activity in apatient in need of such treatment, said method comprising administeringa therapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt thereof.

Embodiments

Embodiment 1. A compound having the formula:

wherein

Ring A is substituted or unsubstituted phenyl or substituted orunsubstituted 5 to 6 membered heteroaryl;

Ring B is substituted or unsubstituted napththyl, substituted orunsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl;

R¹ is independently a halogen, —CX¹ ₃, CHX¹ ₂, —CH₂X¹, —CN, —SO₂Cl,—SO_(n1)R¹⁰, —SO_(v1)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂,—NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸,—OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX¹₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R¹ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R² is independently hydrogen, halogen, —CX² ₃, CHX² ₂, —CH₂X², —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX² ₃, —OCHX² ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R³ is independently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX³ ₃, —OCHX³ ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen, halogen, —CX^(A) ₃,—CHX^(A) ₂, —CH₂X^(A), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX^(A) ₃, —OCHX^(A) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁷ and R⁸ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

z1 is independently an integer from 0 to 4;

m1 and v1 are independently 1 or 2;

n1 is independently an integer from 0 to 4;

X¹, X², X³, and X^(A) are independently —Cl, —Br, —I, or —F.

Embodiment 2. The compound of embodiment 1, having the formula:

wherein

R⁴ is independently a halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —SO₂Cl,—SO_(n4)R¹⁴, —SO_(v4)NR¹¹R¹², —NHNH₂, —ONR¹¹R¹², —NHC═(O)NHNH₂,—NHC═(O)N_(R) ¹¹R¹², —N(O)_(m4), —C(O)R¹³, —C(O)—OR¹³, —C(O)NR¹¹ _(R) ¹²_(, —OR) ¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³, —NR¹¹C═(O)—OR¹³, —NR¹¹OR¹³,—OCX⁴ ₃, —OCHX⁴ ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; twoadjacent R⁴ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R⁵ is independently a halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —SO₂Cl,—SO_(n5)R¹⁸, —SO_(v5)NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵ _(R) ¹⁶, —NHC═(O)NHNH₂,—NHC═(O)NR¹⁵R¹⁶, —N(O)_(m5), —NR¹⁵R¹⁶, —C(O)R¹⁷, —C(O)—OR¹⁷,—C(O)NR¹⁵R¹⁶, —OR¹⁸, —NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷,—NR¹⁵OR¹⁷, —OCX⁵ ₃, —OCHX⁵ ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; twoadjacent R⁵ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

R¹¹, R¹², R¹³, and R¹⁴ are independently hydrogen, halogen, —CX^(B) ₃,—CHX^(B) ₂, —CH₂X^(B), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX^(B) ₃, —OCHX^(B) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹¹ and R¹² substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independently hydrogen, halogen, —CX^(C) ₃,—CHX^(C) ₂, —CH₂X^(C), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX^(C) ₃, —OCHX^(C) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁵ and R¹⁵ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl;

z2 is independently an integer from 0 to 5;

z3 is independently an integer from 0 to 7;

m4, m5, v4 and v5 are independently 1 or 2;

n4 and n5 are independently an integer from 0 to 4;

X⁴, X⁵, X^(B), and X^(C) are independently —Cl, —Br, —I, or —F

Embodiment 3. The compound of one of embodiments 1 to 2, having theformula:

Embodiment 4. The compound of one of embodiments 1 to 2, having theformula:

Embodiment 5. The compound of one of embodiments 1 to 2, having theformula:

Embodiment 6. The compound of one of embodiments 1 to 5, wherein Ring Ais phenyl.

Embodiment 7. The compound of one of embodiments 1 to 5, wherein Ring Ais a 5 to 6 membered heteroaryl.

Embodiment 8. The compound of one of embodiments 1 to 5, wherein Ring Ais a thienyl.

Embodiment 9. The compound of one of embodiments 1 to 5, wherein Ring Ais a 2-thienyl.

Embodiment 10. The compound of one of embodiments 1 to 5, wherein Ring Ais a 3-thienyl.

Embodiment 11. The compound of one of embodiments 1 to 5, wherein Ring Ais a pyridyl.

Embodiment 12. The compound of one of embodiments 1 to 5, wherein Ring Ais a 2-pyridyl.

Embodiment 13. The compound of one of embodiments 1 to 5, wherein Ring Ais a 3-pyridyl.

Embodiment 14. The compound of one of embodiments 1 to 5, wherein Ring Ais a 4-pyridyl.

Embodiment 15. The compound of one of embodiments 1 to 14, wherein RingB is a napththyl.

Embodiment 16. The compound of one of embodiments 1 to 14, wherein RingB is a 1-napththyl.

Embodiment 17. The compound of one of embodiments 1 to 14, wherein RingB is a 2-napththyl.

Embodiment 18. The compound of one of embodiments 1 to 14, wherein RingB is a quinolinyl.

Embodiment 19. The compound of one of embodiments 1 to 14, wherein RingB is a isoquinolinyl.

Embodiment 20. The compound of one of embodiments 1 to 14, wherein RingB is a 1-isoquinolinyl.

Embodiment 21. The compound of one of embodiments 1 to 14, wherein RingB is a 3-isoquinolinyl.

Embodiment 22. The compound of one of embodiments 1 to 14, wherein RingB is a 4-isoquinolinyl.

Embodiment 23. The compound of one of embodiments 1 to 22, wherein R¹ isindependently halogen, —CF₃, CHF₂, CH₂F, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —OCF₃, —OCHF₂, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted 3 to 8membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl.

Embodiment 24. The compound of one of embodiments 1 to 22, wherein R¹ isindependently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 25. The compound of one of embodiments 1 to 22, wherein R¹ isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl.

Embodiment 26. The compound of one of embodiments 1 to 22, wherein R¹ isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy.

Embodiment 27. The compound of one of embodiments 1 to 26, wherein z1 is1.

Embodiment 28. The compound of one of embodiments 1 to 26, wherein z1 is1.

Embodiment 29. The compound of one of embodiments 1 to 28, wherein R⁴ isindependently halogen, —CF₃, CHF₂, —CH₂F, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —OCF₃, —OCHF₂, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted 3 to 8membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl.

Embodiment 30. The compound of one of embodiments 1 to 28, wherein R⁴ isindependently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 31. The compound of one of embodiments 1 to 28, wherein R⁴ isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl.

Embodiment 32. The compound of one of embodiments 1 to 28, wherein R⁴ isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy.

Embodiment 33. The compound of one of embodiments 1 to 32, wherein z2 is1.

Embodiment 34. The compound of one of embodiments 1 to 32, wherein z2 is0.

Embodiment 35. The compound of one of embodiments 1 to 34, wherein R⁵ isindependently halogen, —CF₃, CHF₂, —CH₂F, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —OCF₃, —OCHF₂, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted 3 to 8membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl.

Embodiment 36. The compound of one of embodiments 1 to 34, wherein R⁵ isindependently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 37. The compound of one of embodiments 1 to 34, wherein R⁵ isindependently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl.

Embodiment 38. The compound of one of embodiments 1 to 34, wherein R⁵ isindependently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy.

Embodiment 39. The compound of one of embodiments 1 to 38, wherein z3 is1.

Embodiment 40. The compound of one of embodiments 1 to 38, wherein z3 is0.

Embodiment 41. The compound of one of embodiments 1 to 40, wherein R² isindependently hydrogen, CX² ₃, —CHX² ₂, —CH₂X², —CN, —C(O)H, —C(O)OH,—C(O)NH₂, substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 42. The compound of one of embodiments 1 to 40, wherein R² isindependently hydrogen, unsubstituted methyl, unsubstituted ethyl, orunsubstituted isopropyl.

Embodiment 43. The compound of one of embodiments 1 to 40, wherein R² isindependently hydrogen.

Embodiment 44. The compound of one of embodiments 1 to 43, wherein R³ isindependently hydrogen, CX² ₃, —CHX² ₂, —CH₂X², —CN, —C(O)H, —C(O)OH,—C(O)NH₂, substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 45. The compound of one of embodiments 1 to 43, wherein R³ isindependently hydrogen, unsubstituted methyl, unsubstituted ethyl, orunsubstituted isopropyl.

Embodiment 46. The compound of one of embodiments 1 to 43, wherein R³ isindependently hydrogen.

Embodiment 47. The compound of embodiment 1, having the formula:

Embodiment 48. The compound of embodiment 1, having the formula:

Embodiment 49. The compound of embodiment 1, having the formula:

Embodiment 50. A pharmaceutical composition comprising a compound of oneof embodiments 1 to 49 or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

Embodiment 51. The pharmaceutical composition of embodiment 50, furthercomprising an anti-cancer agent.

Embodiment 52. The pharmaceutical composition of embodiment 51, whereinthe anti-cancer agent is a platinum-based compound.

Embodiment 53. The pharmaceutical composition of embodiment 51, whereinthe anti-cancer agent is a cisplatin.

Embodiment 54. A method of treating a disease associated with PCNAactivity in a patient in need of such treatment, said method comprisingadministering a therapeutically effective amount of a compound of one ofembodiments 1 to 49, or a pharmaceutically acceptable salt thereof.

Embodiment 55. A method of treating cancer in a patient in need of suchtreatment, said method comprising administering a therapeuticallyeffective amount of a compound of one of embodiments 1 to 49, or apharmaceutically acceptable salt thereof.

Embodiment 56. The method of embodiment 55, wherein said cancer isneuroblastoma.

Embodiment 57. A method of inhibiting PCNA activity, said methodcomprising contacting PCNA with an effective amount of a compound of oneof embodiments 1 to 49, or a pharmaceutically acceptable salt thereof.

Embodiments contemplated herein include the following.

Embodiment 1A. A compound having the formula:

wherein Ring A is substituted or unsubstituted phenyl or substituted orunsubstituted 5 to 6 membered heteroaryl; Ring B is substituted orunsubstituted napththyl, substituted or unsubstituted quinolinyl, orsubstituted or unsubstituted isoquinolinyl; R¹ is independently ahalogen, —CX¹ ₃, —CHX'₂, —CH₂X¹, —CN, —SO₂Cl, —SO_(n1)R¹⁰,—SO_(vi)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂, —NHC═(O)NR⁷R⁸,—N(O)_(m1), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —NR⁷SO₂R¹⁰,—NR⁷C═(O)R⁹, —NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX'₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R¹ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² is independently hydrogen,halogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX² ₃, —OCHX² ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is independently hydrogen, halogen, —CX³ ₃,—CHX³ ₂, —CH₂X³, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX³ ₃, —OCHX³ ₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen, halogen,—CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX^(A) ₃, —OCHX^(A) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁷ and R⁸ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; z1 is independently an integer from 0 to 4; m1 and v1 areindependently 1 or 2; n1 is independently an integer from 0 to 4; X¹,X², X³, and X^(A) are independently —Cl, —Br, —I, or —F.

Embodiment 2A. The compound of embodiment 1A, having the formula:

Wherein R⁴ is independently a halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN,—SO₂Cl, —SO_(n4)R¹⁴, —SO_(v4)NR¹¹R¹², —NHNH₂, —ONR¹¹R¹², —NHC═(O)NHNH₂,—NHC═(O)NR¹¹R¹², —N(O)_(m4), —C(O)R¹³, —C(O)—OR¹³, —C(O)NR¹¹R¹², —OR¹⁴,NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³, —NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX⁴ ₃, —OCHX⁴ ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R⁴ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ isindependently a halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —SO₂Cl,—SO_(n5)R¹⁸, —SO_(v5)NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵R¹⁶, —NHC═(O)NHNH₂,—NHC═(O)NR¹⁵R¹⁶, —N(O)_(m5), —NR¹⁵R¹⁶, —C(O)R^(17,) —C(O)—OR¹⁷,—C(O)NR¹⁵R¹⁶, —OR¹⁸, —NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷,—NR¹⁵OR¹⁷, —OCX⁵ ₃, —OCHX⁵ ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; twoadjacent R⁵ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(11, R12,) R^(13,) and R¹⁴ are independentlyhydrogen, halogen, —CX^(B) ₃, —CHX^(B) ₂, —CH₂X^(B), —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(B) ₃, —OCHX^(B) ₂, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹¹ andR¹² substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; R¹⁵, R^(16,) R¹⁷, and R¹⁸ areindependently hydrogen, halogen, —CX^(C) ₃, —CHX^(C) ₂, —CH₂X^(C), —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCX^(C) ₃, —OCHX^(C) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁵and R¹⁶ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; z2 is independently an integerfrom 0 to 5; z3 is independently an integer from 0 to 7; m4, m5, v4 andv5 are independently 1 or 2; n4 and n5 are independently an integer from0 to 4; X⁴, X⁵, X^(B), and X^(C) are independently —Cl, —Br, —I, or —F.

Embodiment 3A. The compound of one of embodiments 1A to 2A, having theformula:

Embodiment 4A. The compound of one of embodiments lA to 2A, having theformula:

Embodiment 5A. The compound of one of embodiments lA to 2A, having theformula:

Embodiment 6A. The compound of one of embodiments lA to 5A, wherein R¹is independently halogen, —CF₃, CHF₂, —CH₂F, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —OCF₃, —OCHF₂, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted 3 to 8 membered heterocycloalkyl, substituted orunsubstituted C₆-C₁₀ aryl, or substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment 7A. The compound of one of embodiments lA to 5A, wherein R¹is independently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 8A. The compound of one of embodiments 1A to 5A, wherein R¹is independently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl.

Embodiment 9A. The compound of one of embodiments 1A to 5A, wherein R¹is independently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy.

Embodiment 10A. The compound of one of embodiments 1A to 9A, wherein z1is 1.

Embodiment 11A. The compound of one of embodiments 1A to 9A, wherein z1is 0.

Embodiment 12A. The compound of one of embodiments 1A to 11A, wherein R⁴is independently halogen, —CF₃, CHF₂, CH₂F, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —OCF₃, —OCHF₂, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted 3 to 8 membered heterocycloalkyl, substituted orunsubstituted C₆-C₁₀ aryl, or substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment 13A. The compound of one of embodiments 1A to 11A, wherein R⁴is independently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 14A. The compound of one of embodiments 1A to 11A, wherein R⁴is independently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl.

Embodiment 15A. The compound of one of embodiments lA to 11A, wherein R⁴is independently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy.

Embodiment 16A. The compound of one of embodiments lA to 11A, wherein R⁴is independently —OR¹⁴.

Embodiment 17A. The compound of embodiment 16A, wherein R¹⁴ is hydrogenor substituted or unsubstituted alkyl.

Embodiment 18A. The compound of embodiment 16A, wherein R¹⁴ is hydrogenor unsubstituted alkyl.

Embodiment 19A. The compound of embodiment 16A, wherein R¹⁴ is hydrogenor unsubstituted C₁-C₅ alkyl.

Embodiment 20A. The compound of embodiment 16A, wherein R¹⁴ is hydrogenor unsubstituted C₁-C₃ alkyl.

Embodiment 21A. The compound of embodiment 16A, wherein R¹⁴ is hydrogenor methyl.

Embodiment 22A. The compound of one of embodiments 1A to 21A, wherein z2is 1.

Embodiment 23A. The compound of one of embodiments 1A to 21A, wherein z2is 0.

Embodiment 24A. The compound of one of embodiments 1A to 23A, wherein R⁵is independently halogen, —CF₃, CHF₂, —CH₂F, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —OCF₃, —OCHF₂, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted 3 to 8 membered heterocycloalkyl, substituted orunsubstituted C₆-C₁₀ aryl, or substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment 25A. The compound of one of embodiments 1A to 23A, wherein R⁵is independently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 26A. The compound of one of embodiments 1A to 23A, wherein R⁵is independently halogen, —OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, orunsubstituted 2 to 4 membered heteroalkyl.

Embodiment 27A. The compound of one of embodiments 1A to 23A, wherein R⁵is independently halogen, —OH, unsubstituted methyl, or unsubstitutedmethoxy.

Embodiment 28A. The compound of one of embodiments 1A to 27A, wherein z3is 1.

Embodiment 29A. The compound of one of embodiments 1A to 27A, wherein z3is 0.

Embodiment 30A. The compound of one of embodiments 1A to 29A, wherein R²is hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN, —C(O)H, —C(O)OH, —C(O)NH₂,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted 2to 6 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 31A. The compound of one of embodiments 1A to 29A, wherein R²is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstitutedisopropyl.

Embodiment 32A. The compound of one of embodiments 1A to 29A, wherein R²is hydrogen.

Embodiment 33A. The compound of one of embodiments 1A to 32A, wherein R³is hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN, —C(O)H, —C(O)OH, —C(O)NH₂,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted 2to 6 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 34A. The compound of one of embodiments 1A to 32A, wherein R³is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstitutedisopropyl.

Embodiment 35A. The compound of one of embodiments 1A to 32A, wherein R³is hydrogen.

Embodiment 36A. The compound of one of embodiments 1A to 35A, whereinRing A is phenyl.

Embodiment 37A. The compound of one of embodiments 1A to 35A, whereinRing A is a 5 to 6 membered heteroaryl.

Embodiment 38A. The compound of one of embodiments 1A to 35A, whereinRing A is a thienyl.

Embodiment 39A. The compound of one of embodiments 1A to 35A, whereinRing A is a 2-thienyl.

Embodiment 40A. The compound of one of embodiments 1A to 35A, whereinRing A is a 3-thienyl.

Embodiment 41A. The compound of one of embodiments 1A to 35A, whereinRing A is a pyridyl.

Embodiment 42A. The compound of one of embodiments 1A to 35A, whereinRing A is a 2-pyridyl.

Embodiment 43A. The compound of one of embodiments 1A to 35A, whereinRing A is a 3-pyridyl.

Embodiment 44A. The compound of one of embodiments 1A to 35A, whereinRing A is a 4-pyridyl.

Embodiment 45A. The compound of one of embodiments 1A to 44A, whereinRing B is a napththyl.

Embodiment 46A. The compound of one of embodiments 1A to 44A, whereinRing B is a 1-napththyl.

Embodiment 47A. The compound of one of embodiments 1A to 44A, whereinRing B is a 2-napththyl.

Embodiment 48A. The compound of one of embodiments 1A to 44A, whereinRing B is a quinolinyl.

Embodiment 49A. The compound of one of embodiments 1A to 44A, whereinRing B is a isoquinolinyl.

Embodiment 50A. The compound of one of embodiments 1A to 44A, whereinRing B is a 1-isoquinolinyl.

Embodiment 51A. The compound of one of embodiments 1A to 44A, whereinRing B is a 3-isoquinolinyl.

Embodiment 52A. The compound of one of embodiments 1A to 44A, whereinRing B is a 4-isoquinolinyl.

Embodiment 53A. The compound of one of embodiments 1A to 35A, having theformula:

Embodiment 54A. The compound of one of embodiments 1A to 35A, having theformula:

Embodiment 55A. The compound of one of embodiments 1A to 35A, having theformula:

Embodiment 56A. The compound of one of embodiments 1A to 23A, having theformula:

Embodiment 57A. The compound of one of embodiments 1A to 23A, having theformula:

Embodiment 58A. The compound of one of embodiments 1A to 23A, having theformula:

Embodiment 59A. The compound of embodiment 1A, having the formula:

Embodiment 60A. The compound of embodiment 1A, having the formula:

Embodiment 61A. The compound of embodiment 1A, having the formula:

Embodiment 62A. The compound of embodiment 1A, having the formula:

Embodiment 63A. The compound of embodiment 1A, having the formula:

Embodiment 64A. The compound of embodiment 1A, having the formula:

Embodiment 65A. The compound of embodiment 1A, having the formula:

Embodiment 66A A pharmaceutical composition comprising a compound of oneof embodiments 1A to 65A or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

Embodiment 67A. The pharmaceutical composition of embodiment 66A,further comprising an anti-cancer agent.

Embodiment 68A. The pharmaceutical composition of embodiment 67A,wherein the anti-cancer agent is a platinum-based compound.

Embodiment 69A. The pharmaceutical composition of embodiment 67A,wherein the anti-cancer agent is a cisplatin.

Embodiment 70A. A method of treating a disease associated with PCNAactivity in a patient in need of such treatment, said method comprisingadministering a therapeutically effective amount of a compound of one ofembodiments 1A to 65A, or a pharmaceutically acceptable salt thereof.

Embodiment 71A. A method of treating cancer in a patient in need of suchtreatment, said method comprising administering a therapeuticallyeffective amount of a compound of one of embodiments 1A to 65A, or apharmaceutically acceptable salt thereof.

Embodiment 72A. The method of embodiment 71A, wherein said cancer isbrain cancer.

Embodiment 73A. The method of embodiment 71A, wherein said cancer isneuroblastoma.

Embodiment 74A. A method of inhibiting PCNA activity, said methodcomprising contacting PCNA with an effective amount of a compound of oneof embodiments lA to 65A, or a pharmaceutically acceptable salt thereof.

Additional Embodiments

Embodiment 1W. A compound having the formula:

wherein

Ring A is substituted or unsubstituted phenyl or substituted orunsubstituted 5 to 6 membered heteroaryl;

Ring B is substituted or unsubstituted napththyl, substituted orunsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl;

R¹ is independently a halogen, —CX¹ ₃, CHX¹ ₂, —CH₂X¹, —CN, —SO_(n1)R¹⁰,—SO_(v1)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂, NHC═(O)NR⁷R⁸, —N(O)_(m1),—NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, -OR¹⁰, —NR⁷SO₂R¹⁰ , —NR⁷C═(O)R⁹,—NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX¹ ₂, —OCH₂X¹, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R¹ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R² is independently hydrogen, halogen, —CX² ₃, CHX² ₂, —CH₂X², —CN,—COOH, —CONH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R³ is independently hydrogen, halogen, —CX³3, CHX³ ₂, —CH₂X³, —CN,—COOH, —CONH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁷, R⁸, R⁹, and R¹⁰ are independently hydrogen, halogen, —CX^(A) ₃,—CHX^(A) ₂, —CH₂X^(A), —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁷ and R⁸ substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

z1 is independently an integer from 0 to 4;

m 1 and v 1 are independently 1 or 2;

n1 is independently an integer from 0 to 4;

X¹, X², X³, and X^(A) are independently —Cl, —Br, —I, or —F.

Embodiment 2W. The compound of embodiment 1W, having the formula:

wherein

R⁴ is independently a halogen, —CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN,—SO_(n4)R¹⁴, —SO_(v4)NR¹¹ _(R) ¹², —NHNH₂, —ONR¹¹ _(R) ¹²,—NHC═(O)NHNH₂, —NHC═(O)NR¹¹ _(R) ¹², —N(O)_(m4, —NR) ¹¹ _(R) ¹²,—C(O)R¹³, —C(O)—OR¹³, —C(O)NR¹¹R¹², —OR¹⁴, NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R⁴ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R⁵ is independently a halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN,—SO_(n5)R¹⁸, —SO_(v5)NR¹⁵R¹⁶, —NHNH₂, —ONR¹⁵R¹⁶, —NHC═(O)NHNH₂,—NHC═(O)NR¹⁵R¹⁶, —N(O)_(m5, —NR) ¹⁵R¹⁶, —C(O)R¹⁷, —C(O)—OR¹⁷,—C(O)NR¹⁵R¹⁶, —OR¹⁸, NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)R¹⁷, —NR¹⁵C(O)—OR¹⁷,—NR¹⁵OR¹⁷, —OCX⁵ ₃, —OCHX⁵ ₂, —OCH₂X⁵, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; two adjacent R⁵ sub stituents may optionally be joined toform a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R¹¹, R¹², R¹³, and R¹⁴ are independently hydrogen, halogen, —CX^(B) ₃,—CHX^(B) ₂, —CH₂X^(B), —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R¹¹ and R¹² substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independently hydrogen, halogen, —CX^(C) ₃,—CHX^(C) ₂, —CH₂X^(C), —CN, —COOH, —CONH₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R¹⁵ and R¹⁶ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl;

z2 is independently an integer from 0 to 5;

z3 is independently an integer from 0 to 7;

m4, m5, v4 and v5 are independently 1 or 2;

n4 and n5 are independently an integer from 0 to 4;

X⁴, X⁵, X^(B), and X^(C) are independently —Cl, —Br, —I, or —F.

Embodiment 3W. The compound of one of embodiments 1W to 2W, having theformula:

Embodiment 4W. The compound of one of embodiments 1W to 2W, having theformula:

Embodiment 5W. The compound of one of embodiments 1W to 2W, having theformula:

Embodiment 6W. The compound of one of embodiments 1W to 5W, wherein R¹is independently halogen, —CF₃, CHF₂, CH₂F, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —OCF₃, —OCHF₂, —OCH₂F, substituted or unsubstitutedC₁-C₅ alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted 3 to 8 membered heterocycloalkyl, substituted orunsubstituted C₆-C₁₀ aryl, or substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment 7W. The compound of one of embodiments 1W to 5W, wherein R¹is independently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 8W. The compound of one of embodiments 1W to 5W, wherein R¹is independently halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F,—OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4membered heteroalkyl.

Embodiment 9W. The compound of one of embodiments 1W to 5W, wherein R¹is independently halogen, —OH, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂,—OCH₂F, unsubstituted methyl, or unsubstituted methoxy.

Embodiment 10W. The compound of one of embodiments 1W to 9W, wherein z1is 1.

Embodiment 11W. The compound of one of embodiments 1W to 9W, wherein z1is 0.

Embodiment 12W. The compound of one of embodiments 1W to 11W, wherein R⁴is independently halogen, —CF₃, —CHF₂, —CH₂F, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —OCF₃, —OCHF₂, —OCH₂F, substituted or unsubstitutedC₁-C₅ alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted 3 to 8 membered heterocycloalkyl, substituted orunsubstituted C₆-C₁₀ aryl, or substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment 13W. The compound of one of embodiments 1W to 11W, wherein R⁴is independently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 14W. The compound of one of embodiments 1W to 11W, wherein R⁴is independently halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F,—OH, —NH₂, —SH, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4membered heteroalkyl.

Embodiment 15W. The compound of one of embodiments 1W to 11W, wherein R⁴is independently halogen, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F,—OH, unsubstituted methyl, or unsubstituted methoxy.

Embodiment 16W. The compound of one of embodiments 1W to 11W, wherein R⁴is independently —OR¹⁴.

Embodiment 17W. The compound of embodiment 16W, wherein R¹⁴ is hydrogenor substituted or unsubstituted alkyl.

Embodiment 18W. The compound of embodiment 16W, wherein R¹⁴ is hydrogenor unsubstituted alkyl.

Embodiment 19W. The compound of embodiment 16W, wherein R¹⁴ is hydrogenor unsubstituted CI-CS alkyl.

Embodiment 20W. The compound of embodiment 16W, wherein R¹⁴ is hydrogenor unsubstituted C₁-C₃ alkyl.

Embodiment 21W. The compound of embodiment 16W, wherein R¹⁴ is hydrogenor unsubstituted methyl.

Embodiment 22W. The compound of embodiment 16W, wherein R¹⁴ isunsubstituted methyl.

Embodiment 23W. The compound of one of embodiments 1W to 22W, wherein z2is 1.

Embodiment 24W. The compound of one of embodiments 1W to 22W, wherein z2is 0.

Embodiment 25W. The compound of one of embodiments 1W to 24W, wherein R⁵is independently halogen, —CF₃, CHF₂, CH₂F, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —OCF₃, —OCHF₂, —OCH₂F, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted 3 to 8 membered heterocycloalkyl, substituted orunsubstituted C₆-C₁₀ aryl, or substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment 26W. The compound of one of embodiments 1W to 24W, wherein R⁵is independently halogen, —CF₃, —OH, —NH₂, —SH, substituted orunsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4 memberedheteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, substituted orunsubstituted phenyl, or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment 27. The compound of one of embodiments 1W to 24W, wherein R⁵is independently halogen, —CF₃, CHF₂, CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OH,—NH₂, —SH, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 memberedheteroalkyl.

Embodiment 28W. The compound of one of embodiments 1W to 24W, wherein R⁵is independently halogen, —CF₃, CHF₂, CH₂F, —OCF₃, —OCHF₂, —OCH₂F, —OH,unsubstituted methyl, or unsubstituted methoxy.

Embodiment 29W. The compound of one of embodiments 1W to 28W, wherein z3is 1.

Embodiment 30W. The compound of one of embodiments 1W to 28W, wherein z3is 0.

Embodiment 31W. The compound of one of embodiments 1W to 30W, wherein R²is hydrogen, —CX² ₃, —CHX² ₂, —CH₂X², —CN, —C(O)H, —C(O)OH, —C(O)NH₂,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted 2to 6 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 32W. The compound of one of embodiments 1W to 30W, wherein R²is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstitutedisopropyl.

Embodiment 33W. The compound of one of embodiments 1W to 30W, wherein R²is hydrogen.

Embodiment 34W. The compound of one of embodiments 1W to 33W, wherein R³is hydrogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —CN, —C(O)H, —C(O)OH, —C(O)NH₂,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted 2to 6 membered heteroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 35W. The compound of one of embodiments 1W to 33W, wherein R³is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstitutedisopropyl.

Embodiment 36W. The compound of one of embodiments 1W to 33W, wherein R³is hydrogen.

Embodiment 37W. The compound embodiment 1W, wherein Ring A is asubstituted or unsubstituted phenyl.

Embodiment 38W. The compound of one of embodiments 2W to 36W, whereinRing A is phenyl.

Embodiment 39W. The compound embodiment 1W, wherein Ring A is asubstituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment 40W. The compound of one of embodiments 2W to 36W, whereinRing A is a 5 to 6 membered heteroaryl.

Embodiment 41W. The compound embodiment 1W, wherein Ring A is asubstituted or unsubstituted thienyl.

Embodiment 42W. The compound of one of embodiments 2W to 36W, whereinRing A is a thienyl.

Embodiment 43W. The compound embodiment 1W, wherein Ring A is asubstituted or unsubstituted 2-thienyl.

Embodiment 44W. The compound of one of embodiments 2W to 36W, whereinRing A is a 2-thienyl.

Embodiment 45W. The compound embodiment 1W, wherein Ring A is asubstituted or unsubstituted 3-thienyl.

Embodiment 46W. The compound of one of embodiments 2W to 36W, whereinRing A is a 3-thienyl.

Embodiment 47W. The compound embodiment 1, wherein Ring A is asubstituted or unsubstituted pyridyl.

Embodiment 48W. The compound of one of embodiments 2W to 36W, whereinRing A is a pyridyl.

Embodiment 49W. The compound embodiment 1W, wherein Ring A is asubstituted or unsubstituted 2-pyridyl.

Embodiment 50W. The compound of one of embodiments 2W to 36W, whereinRing A is a 2-pyridyl.

Embodiment 51W. The compound embodiment 1W, wherein Ring A is asubstituted or unsubstituted 3-pyridyl.

Embodiment 52W. The compound of one of embodiments 2W to 36W, whereinRing A is a 3-pyridyl.

Embodiment 53W. The compound embodiment 1W, wherein Ring A is asubstituted or unsubstituted 4-pyridyl.

Embodiment 54W. The compound of one of embodiments 2W to 36W, whereinRing A is a 4-pyridyl.

Embodiment 55W. The compound of embodiment 1W, wherein Ring B is asubstituted or unsubstituted napththyl.

Embodiment 56W. The compound of one of embodiments 2W to 54W, whereinRing B is a napththyl.

Embodiment 57W. The compound of embodiment 1W, wherein Ring B is asubstituted or unsubstituted 1-napththyl.

Embodiment 58W. The compound of one of embodiments 2W to 54W, whereinRing B is a 1-napththyl.

Embodiment 59W. The compound of embodiment 1W, wherein Ring B is asubstituted or unsubstituted 2-napththyl.

Embodiment 60W. The compound of one of embodiments 2W to 54W, whereinRing B is a 2-napththyl.

Embodiment 61W. The compound of embodiment 1W, wherein Ring B is asubstituted or unsubstituted quinolinyl.

Embodiment 62W. The compound of one of embodiments 2W to 54W, whereinRing B is a quinolinyl.

Embodiment 63W. The compound of embodiment 1W, wherein Ring B is asubstituted or unsubstituted isoquinolinyl.

Embodiment 64W. The compound of one of embodiments 2W to 54W, whereinRing B is a isoquinolinyl.

Embodiment 65W. The compound of embodiment 1W, wherein Ring B is asubstituted or unsubstituted 1-isoquinolinyl.

Embodiment 66W. The compound of one of embodiments 2W to 54W, whereinRing B is a 1-isoquinolinyl.

Embodiment 67W. The compound of embodiment 1W, wherein Ring B is asubstituted or unsubstituted 3-isoquinolinyl.

Embodiment 68W. The compound of one of embodiments 2W to 54W, whereinRing B is a 3-isoquinolinyl.

Embodiment 69W. The compound of embodiment 1W, wherein Ring B is asubstituted or unsubstituted 4-isoquinolinyl.

Embodiment 70W. The compound of one of embodiments 2W to 54W, whereinRing B is a 4-isoquinolinyl.

Embodiment 71W. The compound of one of embodiments 1W to 36W, having theformula:

Embodiment 72W. The compound of one of embodiments 1W to 36W, having theformula:

Embodiment 73W. The compound of one of embodiments 1W to 36W, having theformula:

Embodiment 74W. The compound of one of embodiments 1W to 24W, having theformula:

Embodiment 75W. The compound of one of embodiments 1W to 24W, having theformula:

Embodiment 76W. The compound of one of embodiments 1W to 24W, having theformula:

Embodiment 77W. The compound of embodiment 1W, having the formula:

Embodiment 78W. The compound of embodiment 1W, having the formula:

Embodiment 79W. The compound of embodiment 1W, having the formula:

Embodiment 80W. The compound of embodiment 1W, having the formula:

Embodiment 81W. The compound of embodiment 1W, having the formula:

Embodiment 82W. The compound of embodiment 1W, having the formula:

Embodiment 83W. The compound of embodiment 1W, having the formula:

Embodiment 84W. A pharmaceutical composition comprising a compound ofone of embodiments 1W to 83W or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.

Embodiment 85W. The pharmaceutical composition of embodiment 84W,further comprising an anti-cancer agent.

Embodiment 86W. The pharmaceutical composition of embodiment 85W,wherein the anti-cancer agent is a platinum-based compound.

Embodiment 87W. The pharmaceutical composition of embodiment 85W,wherein the anti-cancer agent is a cisplatin.

Embodiment 88W. A method of treating a disease associated with PCNAactivity in a patient in need of such treatment, said method comprisingadministering a therapeutically effective amount of a compound of one ofembodiments 1W to 83W, or a pharmaceutically acceptable salt thereof.

Embodiment 89W. A method of treating cancer in a patient in need of suchtreatment, said method comprising administering a therapeuticallyeffective amount of a compound of one of embodiments 1W to 83W, or apharmaceutically acceptable salt thereof.

Embodiment 90W. The method of embodiment 89W, wherein said cancer isleukemia, lung cancer, colon cancer, a central nervous system cancer,melanoma, ovarian cancer, renal cancer, prostate cancer, or breastcancer.

Embodiment 91W. The method of embodiment 89W, wherein said cancer isnon-small cell lung cancer.

Embodiment 92W. The method of embodiment 89W, wherein said cancer istriple negative breast cancer.

Embodiment 93W. The method of embodiment 89W, wherein said cancer is acentral nervous system cancer.

Embodiment 94W. The method of embodiment 89W, wherein said cancer isbrain cancer.

Embodiment 95W. The method of embodiment 89W, wherein said cancer isneuroblastoma.

Embodiment 96W. A method of inhibiting PCNA activity, said methodcomprising contacting PCNA with an effective amount of a compound of oneof embodiments 1W to 83W, or a pharmaceutically acceptable salt thereof.

Embodiment 97W. The method of embodiment 96W, wherein said contactingincludes contacting a protein of SEQ ID NO:2 with an effective amount ofa compound of one of embodiments 1W to 83W, or a pharmaceuticallyacceptable salt thereof.

Embodiment 98W. The method of embodiment 96W, wherein said contactingincludes contacting a protein of SEQ ID NO:3 with an effective amount ofa compound of one of embodiments 1W to 83W, or a pharmaceuticallyacceptable salt thereof.

Embodiment 99W. The method of embodiment 96W, wherein said contactingincludes contacting a protein of SEQ ID NO:4 with an effective amount ofa compound of one of embodiments 1W to 83W, or a pharmaceuticallyacceptable salt thereof.

F. EXAMPLES

A challenge of developing an anti-cancer therapy for any type of cancerhas always been the ability to selectively destroy cancer cells, whilesparing normal tissue. Most early chemotherapeutic or radiotherapeuticagents target DNA structures or mitotic spindles. Although they killcancer cells effectively, these drugs cause significant side-effects. Incase of treating childhood cancers such as NB, these drugs may give riseto secondary malignancy as well [4]. Following the pioneering andsuccessful example of Gleevec [29], several therapeutic agents targetingspecific oncogenic signaling components have reached the clinic over thepast 15 years [30-35]. Whereas these target-based therapies in generalcause less severe side-effects than early chemotherapeutic agents, drugsthat target individual oncogenes often succumb to the development ofresistance [36-38] by cancer cells through mutations at the targetgenes, alterations in the expression of the target, or by activation ofalternative survival pathways. One way to preempt these types of thedrug resistance inherent to the adaptive and heterogeneous nature ofcancers is to target hub proteins (proteins that influence multiplepathways (e.g., signaling pathways) instead of only a single pathway)which influence the activity of broad cellular machineries, such as, butnot limited to, the DNA replication/repair apparatus, which arenecessary for the growth and survival of all cancer cells withoutcausing unacceptable side-effects in non-malignant cells. Identificationof cancer specific features of essential hub proteins and cellularmachineries may be advantageous.

For example, proliferating cell nuclear antigen (PCNA), which is foundin all eukaryotic cells as an evolutionally conserved protein, is widelyused as a tumor progression marker [7-9] along with Ki67 and has beenidentified to play an essential role in regulating DNA synthesis andrepair as well as its role in cancer cell growth and survival [10].Therefore, it represents an attractive molecular target to developbroad-spectrum anti-cancer agents [11]. A major interaction site in PCNAis the interdomain connecting loop that spans from amino acid M121 toY133 (SEQ ID NO:3) [12]. This loop is recognized by many PIP-boxproteins including p21 (CDKN1A) [13], DNA polymerase 6 (Pol 6) [14], andflap endonuclease 1 (FEN1) [15]. Using 2D-PAGE, we previously reportedthat normal cells and tissues express an isoform of PCNA with a basicisoelectric point (referred to as nmPCNA) [16]. In contrast, cancercells express both the basic and, to a much higher level, a uniqueacidic isoform of PCNA (caPCNA) that is not significantly expressed innon-malignant cells [16]. The isoelectric point differences between thetwo isoforms results from changes in the malignant cells topost-translationally modify the PCNA polypeptide [17], and is not due toan mRNA splice variant or mutation within the PCNA gene. ThecaPCNA-specific antigenic site was mapped to contain a small eight aminoacid peptide region (L126-Y133 (SEQ ID NO:4) within the interconnectordomain of PCNA [16]. Interestingly, the L126-Y133 region is onlyaccessible to immunohistochemistry staining by both a polyclonal and amonoclonal antibody specific to this region in tumor cells [16],suggesting that this region is structurally altered and becomes moreaccessible for protein-protein interaction in tumor cells, whichpredominantly express the caPCNA isoform. Using a cell permeable peptideharboring this eight amino acid sequence to block PCNA interactions, NBcells were selectively killed [18]. Consistent with the tumor-associatedexpression pattern of caPCNA [16], the peptide doesn't cause significanttoxicity to non-malignant cells, including human neural crest stem cells[18].

In summary, there is a significant medical need for new therapies toimprove the treatment outcomes of this aggressive cancer. In addition,new molecular targets such as PCNA also need to be further evaluated todetermine their use as therapeutic targets for cancer treatment.

The alteration in structure and accessibility in the L126-Y133 region ofcaPCNA offers a structural basis for developing small molecules thatspecifically target caPCNA and are therefore selectively toxic to cancercells. To translate these biological and structural insights into drugdiscovery, a virtual screen for compounds that target the binding pocketdelineated by residues L126 and Y133 in PCNA was performed. Reportedherein is the identification of a small molecule compound, whichselectively kills NB cells at a low micromolar concentration and thedevelopment of AOH1160, which has a significantly improved potency andtherapeutic window over prior compounds. Mechanistically, AOH1160competes with T3, a known PCNA ligand [19], for binding to PCNA. Itinterferes with DNA replication and blocks homologous recombination (HR)mediated DNA repair, leading to cell cycle arrest, accumulation ofunrepaired DNA damages, and enhanced sensitivity to cisplatin treatment.Therapeutically, AOH1160 is orally available to animals and suppressestumor growth without causing significant weight loss in mice. Insummary, our study demonstrated the feasibility of targeting PCNA, whichis central to broad cellular processes and indispensible to the growthand survival of all cancer cells, without causing unacceptable toxicity.The favorable pharmacologic and therapeutic properties of AOH1160demonstrate the potential of this compound as a novel therapeutic agentfor treating NB.

Example 1. Identification of PCNA Inhibitors by Computer Modeling

The virtual screen is based on the known crystal structures of thePCNA/FEN1 complex that are available from the RCSB protein database andfocuses on the binding pocket in PCNA delineated by residues betweenL126 and Y133 of PCNA (see FIG. 1D). Chemical databases available at theAlbany Molecular Research Institute (AMRI, Albany, NY) were screened.The databases contain 300,000 chemical compounds available directly fromAMRI in at least 2 mg quantities and more than 6.5 million additionalcompounds available from external vendors. For more than 3 milliondrug-like compounds in the databases, multiple conformations werepre-computed and a combination of substructure and pharmacophoresearches using tools in the MOE software (Chemical Computing Group,Montreal, Canada, MOE v2008.05) was performed. The initial virtualscreen yielded more than 8,000 hits. These hits were further analyzed bymolecular docking studies using the computer program, Glide(Schrodinger, LLC, New York, N.Y., Impact v 50207) [20] and 57 compoundswere selected for acquisition and experimental testing.

Development of a computer model for compound optimization. A computermodel for compound optimization was initially built by theAll-Around-Docking (AAD) methodology, which allows a small molecule tosearch the whole surface of the target protein for the binding site thathas the lowest docking score by utilizing Schördinger Glide [20]. Themodel was further refined by 50 ns metadynamics simulation and minimizedthe initial docking pose by the NAMD software [21].

Example 2. Plasmids and Cell Lines

The human NB cell lines, SK-N-DZ, SK-N-BE(2)c, SK-N-AS, and LAN-5obtained from the American Type Culture Collection (Rockville, Md.),were cultured in DMEM with 10% fetal bovine serum (FBS), 100 units/mlpenicillin, and 100 μg/ml streptomycin in the presence of 5% CO₂ at 37°C. Human PBMCs from a healthy donor were purchased from SanguineBioSciences (Valencia, Calif.) and grown in RPMI1640 with 10% FBS, 100units/ml penicillin, 100 μg/ml streptomycin, and 10 ng/ml IL-2 in thepresence of 5% CO₂ at 37° C. Human embryonic progenitor cell line7SM0032 was acquired from Millipore (Billerica, Mass.) and grown in thehEPM-1 Media Kit purchased from the same company. The plasmid pCBASceexpresses the rare cutting I-SceI meganuclease [22]. The U20S-derivedcell lines, DR-GFP and EJ5-GFP, each contain a stably transfectedreporter gene for DSB repair mediated by HR and end joining (EJ),respectively [23]. These cell lines were cultured in DMEM medium with10% FBS at 37° C. in the presence of 5% CO₂.

Example 3. Cell Growth and Terminal DeoxynucleotidylTransferase-Mediated dUTP Nick end Labeling (TUNEL) Assays.

To measure the effect of the compounds on cell growth, cells were seededat 3×10⁴/ml into a 96-well plate. Once attached, cells were treated withvarious concentrations of AOH1160 for 72 h. Cell growth was measured bythe CellTitor-Glo assay (Promega, Madison, Wis.) according to themanufacturer's instructions. To measure apoptosis, cells were seeded at1×10⁵/ml onto a chamber slide. Once attached, cells were treated withthe 500 nM AOH1160 for 24 h. Cells were fixed and analyzed by a TUNELassay using the TMR red in situ cell death detection kit (RocheDiagnostics, Indianapolis, Ind.).

Example 4. Cell Cycle Analysis

Cells were seeded at 1×10⁵/ml in a 6-well plate. Once attachedovernight, cells were treated with or without AOH1160 for 6 or 24 h.After being fixed in 60% ethanol and stained with propidium iodide (PI),cells were analyzed by flow cytometry to determine the cellular PIfluorescence intensity. The flow cytometry data were analyzed by theFlowJo program to model various cell populations.

Example 5. DSB Repair Assays

DR-GFP and EJ5-GFP cell lines were seeded at 2.5×10⁴ cells/cm² in a12-well plate. Once attached overnight, cells were transfected with thepCBASce plasmid that expresses I-SceI by Lipofectamine 2000(Invitrogen). After incubation for 3 h, the media containingtransfection complexes was aspirated and replaced with fresh mediacontaining AOH1160. The HR and EJ-mediated DSB repair, indicated by therestoration of a functional GFP gene in the respective cell lines, werequantified by measuring the relative abundance of GFP-positive cells byflow cytometry 3 days after transfection.

Example 6. Saturation Transfer Difference (STD) Nuclear MagneticResonance (NMR)

Recombinant human PCNA was purified and exchanged to D20-based phosphatebuffered saline (PBS), pH 7.2. T3 purchased from Sigma (Saint Louis, MO)and AOH1160 synthesized in house were dissolved in D6-DMSO and stored at−20° C. freezer. The STD NMR experiments were carried out in thepresence of 1 μM PCNA, 20 μM Deuterated-DTT, 0.02% NaN3, and 2% D6-DMSOwith T3 and/or AOH1160. The reference spectra were acquired under thesame condition without PCNA. 5uM DSS was used as an internal referenceto determine the reported ligand concentration in solution. All NMRexperiments were carried out at 25° C. on 600 MHz Bruker Avance equippedwith 5 mm triple resonance cryogenic probe. STD (Saturation TransferDifference) NMR spectra were acquired with transients ranging from 2560to 32000, spectral width 8012 Hz with 24 k data points. The recycledelay was 2.8 s. Selective saturation was composed of 50 gauss shapedpulses at a field strength of 86Hz, and the duration of each pulse is 50ms with a 500 μs delay between pulses. The spin lock filter used tosuppress protein signal was optimized to 60 ms at field strength of 5kHz. The frequency for protein saturation was optimized to be 0.9 ppm;the ligand signals were not disturbed with the employed selectivesaturation condition at this frequency. The reference spectrum wasacquired with saturation irradiated at −30ppm. To eliminate potentialartifacts, the saturation and reference experiments were acquired in aninterleaved manner, and the finished experiments were separated into two1D data for analysis. The peak integration was carried out with BrukerTopspin software. The STD effect was described using equation(IRef−ISTD)/IRef, in which the IRef is the peak intensity from thereference experiment, and the ISTD is the peak intensity from theon-resonance saturation experiment.

Example 7. Human Thyroid Hormone Receptor Beta (TRβ) reporter assay.

Reporter cells constitutively expressing human TRβ and containing aluciferase reporter gene functionally linked to a TRβ-responsivepromoter were purchased from Indigo Biosciences (State College, Pa.).Cells were treated by various concentration of T3 or AOH1160 for 24hours. The effect of each compound on TRβ activity was examined bymeasuring the luciferase reporter gene expression according to themanufacturer's instruction.

Example 8. Clonogenic Assay

Three hundred human SK-N-DZ NB cells were seeded onto a 60-mm tissueculture dish. Once attached overnight, cells were treated with orwithout various concentrations of cisplatin in the presence or absenceof 500 nM of AOH1160 for 18 h. Cells were washed twice with growthmedium and were cultured in fresh medium for 3 weeks to allow survivingcells to form colonies. The medium was changed every 3 days throughoutthe experiment. The colonies formed under each treatment conditions werecounted after being stained with 0.5% crystal violet.

Example 9. Western Blot

Cells were dissolved into the Laemmli sample buffer on the plate. Thewhole cell extracts were sonicated, and the proteins in the lysate wereresolved using a 4-12% SDS polyacrylamide gel, and the resolved proteinswere blotted onto a nitrocellulose membrane. Antibodies specific toH2A.X, cleaved caspase-3, full-length caspase-3, or cleaved caspase-9were purchased from Cell Signaling Technology (Danvers, Mass.). Theanti-γH2A.X antibody was purchased from Millipore. The membrane wasblocked with 5% nonfat dry milk and incubated individually with each ofthese antibodies dissolved in the blocking buffer. After incubation withperoxidase-conjugated secondary antibodies, the protein of interest wasdetected using an ECL kit purchased from Thermo Fisher Scientific(Waltham, Mass.).

Example 10. In Vivo Tumor Model

All experiments involving live animals were carried out in strictaccordance with the recommendations in the Guide for the Care and Use ofLaboratory Animals of the National Institutes of Health. The protocol(#11034) was reviewed and approved by the City of Hope InstitutionalAnimal Care and Use Committee. Nude mice 6-8 weeks of age were purchasedfrom the Jackson Laboratory (Bar Harbor, Me.). SK-N-BE(2)c cells wereharvested and washed twice in PBS. Cells were suspended in Matrigel (BDBiosciences) at 5×10⁷/ml. 0.1 ml of suspended cells was subcutaneouslyinjected into the right flank of each of 40 nude mice. A dosing solutionof 5 mg/ml AOH1160 was preparing by dissolving an appropriate amount ofAOH1160 in a dosing vehicle of 1% carboxymethyl cellulose and 0.5% Tween80. Mice were randomly grouped into two groups with 20 mice in eachgroup. The mice were treated with 30 mg/kg AOH1160 or vehicle twice aday by gavages throughout the entire experiment starting one day aftertumor cell injection. Mice were monitored twice weekly for any sign ofside effects. The weight of the animals was measured as an indicator ofcompound toxicity. At the end of the experiment, tumors were isolatedfrom sacrificed mice and their masses were measured.

Example 11. Identification and Characterization of Compounds

To identify small molecule compounds that target the PCNA and FEN1interface, we started with known crystal structures of the PCNA/FEN1complex that are available from the RCSB protein database. To improvethe likelihood of identifying novel small molecules that specificallytarget caPCNA, we focused our virtual screen on the binding pocket inPCNA delineated by residues L126 and Y133 and screened databasesconsisting of more than 6.8 million chemical structures available at theAMRI. A set of 57 compounds identified by the virtual screen wasacquired and further tested in a cell viability assay. A compound(AOH39) was selected for further development due to its anti-canceractivity and selectivity. The compound is toxic to multiple NB celllines with IC₅₀ ranging from 1.3 to 2.8 μM. It's much less toxic tonon-malignant cells including human peripheral blood mononuclear cells(PBMC) and human neural crest stem cells (7SM0032) with IC₅₀ of 15.4 μMand about 100 μM on these cells respectively, indicating that thiscompound selectively inhibits the growth of NB cancer cells.

To explore possible mechanisms for the compound anti-tumor activity, weperformed cell cycle analysis and found that the compound treatmentcaused cell cycle arrest at the S and G2 phases, suggesting aninterference of DNA replication and repair. As early as 24 hours aftertreatment, cells start to die through apoptosis as indicated by the riseof a sub-G1 cell population. The S and G2 arrest by treatment coincideswith enhanced intracellular γH2A.X levels, indicating an accumulation ofdouble stranded DNA breaks (DSB). DSB's, if not resolved in time, arelethal to cells. Cells deal with double-stranded DNA breaks mainlythrough EJ-mediated DNA repair pathways in G1 phase and HR-mediatedpathways during S and G2 phases [24, 25]. Reporter cell lines have beenestablished to monitor each of these DNA repair pathways [23]. Thesecells lines each contain a GFP reporter cassette disrupted by aninsertion of recognition site(s) for the endonuclease I-SceI.Introduction of exogenous I-SceI creates DSB(s) within the reporters.Each reporter is designed such that repair of the I-SceI-induced DSB(s)by a specific pathway can result in restoration of the GFP cassette: HRfor DR-GFP and EJ for EJ5-GFP. The relative abundance of GFP-positivecells determined by flow cytometry, therefore, reflects the efficiencyof the respective DSB repair pathways in these reporter cell lines.Using these characterized reporter cell lines, we observed thattreatment inhibited HR-mediated DNA repair, without exerting anystatistically significant effect on EJ. Collectively, these resultssuggest that the compound interferes with DNA synthesis and HR-mediatedDNA repair, causing accumulation of DNA damage and S and G2 cell cyclearrest.

Example 12. A0111160 is Surprisingly Improved Over the Prior Compound

To improve the anti-tumor potency of the compound while preserving itsfavorable selectivity, a series of compounds were synthesized andtested. One compound (AOH1160) (FIG. 1A) is significantly more potentthan the prior compound in killing NB cells with IC₅₀s ranging 0.18 μMto 0.22 μM (FIG. 1B). Furthermore, AOH1160 is less toxic tonon-malignant PBMC and 7SM0032 cells than AOH39. The combinedimprovements in potency and selectivity lead to a significantimprovement in the therapeutic window (FIG. 1B). AOH1160 was tested in abroad range of non-malignant cells, including human primary mammaryepithelial and small airway epithelial cells, and no significanttoxicity was found in these cells up to a concentration of 10 μM.Although AOH1160 shares certain sub-structural similarity with T3 andT2AA, both known PCNA ligands with significant thyroid hormone (TR)activities [19], AOH1160 did not show any thyroid hormone activity in aTR reporter assay (FIG. 1C).

In addition numerous analogs related to AOH1160 were screened innumerous neuroblastoma cell lines for anti-cancer activity (Table 2).AOH1160 was screened for anti-cancer activity in additional cancer celllines besides neuroblastoma (Table 3).

To gain further structural insight into the binding of AOH1160 to PCNA,an in-house computer program based on the All-Around-Docking (AAD)methodology [20] was employed to model the best binding site and thebinding pose of AOH1160. In contrast to the virtual screen strategy thatfocused on the binding pocket delineated by L126 and Y133, the AADapproach allows a small molecule to search the whole surface of thetarget protein for the binding site that has the lowest docking score.The AAD docking method was validated by modeling the binding of T3, aknown PCNA inhibitor [19], to PCNA. The T3 model pose predicted by theprogram is only 0.47 Å in root mean square deviation (RMSD) from what'sindicated by the crystallographic study of the T3/PCNA complex (PDB:3vkx), indicating that the calculation fits well with crystallographicresults. Using this program, it was found that AOH1160 binds to the samebinding pocket as T3 does on PCNA (FIG. 1D). The model also indicatedthat the binding affinitiy of AOH1160 and AOH39 to PCNA are −5.54kcal/mol and −4.62 kcal/mol respectively, indicating approximately a5-fold enhancement in binding affinity of AOH1160 to PCNA over that ofAOH39. The calculated difference in PCNA binding affinity agrees wellwith the 6-7 fold increase in compound potency observed in cellviability assays (FIG. 1B).

To verify whether AOH1160 competes with T3 in binding to PCNA, theinteraction of both compounds with PCNA was analyzed by a SaturationTransfer Difference (STD) NMR experiment [26]. STD NMR is a technique todetect binding of small ligands to large proteins by observing theresulted suppression of NMR signals of the small ligands. The STD NMRexperiment of T3 revealed that binding of T3 to PCNA results in a moredramatic signal reduction at protons d, e, and f than at protons a and b(FIG. 1E, spectrum 1 and 2), indicating that the aromatic ringcontaining protons d, e and f of T3 forms more intimate contact withPCNA than the rest of T3. This structural pose is consistent with thecrystal structure of T3 in complex with PCNA (PDB: 3VKX). AOH1160significantly reduced the STD of T3, as indicated by less reduction ofprotons d, e, and f signals in the presence of AOH1160 than in itsabsence (FIG. 1E, spectrum 4 and 2), indicating that AOH1160 competeswith T3 for binding to PCNA. The ability of 3.2 μM AOH1160 toeffectively compete with 29 μM T3 is consistent with the fact thatAOH1160 is a much more potent compound than T3 in a cell viability assay([19] and FIG. 1B).

Example 13. AOH1160 Induces Cell Cycle Arrest, Accumulation of DNADamage, and Apoptosis at Sub-Micromolar Concentrations

AOH1160 causes cell cycle arrest (FIG. 2A), increases γH2A.X levels(FIG. 2B), and apoptosis as indicated by the increase in the sub-G1population (FIG. 2A) and TUNEL positivity (FIG. 2B) in NB cells. Theincrease in apoptosis in NB cells coincides with activation of caspase-3and caspase-9, suggesting the involvement of these two caspases inAOH1160-induced apoptosis. Consistent with its lack of toxicity tonon-malignant cells in a cell viability assay, AOH1160 doesn'tsignificantly change the cell cycle profiles of 7SM0032 cells (FIG. 2A).Nor does it increase intracellular γH2A.X level (FIG. 2B) or causeapoptosis in 7SM0032 cells (FIG. 2C and 2D).

Example 14. AOH1160 Inhibits HR-Mediated DSB Repair and Sensitizes NBCells to Cisplatin

AOH1160 blocks DNA repair in DR-GFP, but not in EJ5-GFP cells,indicating that it selectively inhibits HR-mediated DNA repair (FIG. 3Aand 3B). HR-mediated DNA repair plays an important role in repairingcross-linked DNA caused by chemotherapeutic drugs, such as cisplatin[27, 28]. A clonogenic assay was performed to investigate whetherAOH1160 would increase NB cells' sensitivity to cisplatin. SK-N-DZ cellswere treated with or without various concentrations of cisplatin in thepresence or absence of 500 nM of AOH1160 for 18 hours. Cells were washedand cultured in fresh medium in the absence of either agent for 3 weeksto allow colony formation. As shown in FIG. 5, SK-N-DZ cells are moresensitive to cisplatin treatment in the presence of AOH1160 than in itsabsence, demonstrating the potential of combining AOH1160 withconventional chemotherapeutic drugs in treating NB patients.

Example 15. AOH1160 Inhibits Tumor Growth in Animals

Given the potency and the favorable therapeutic properties of AOH1160,its efficacy was tested in nude mice bearing xenograft tumors derivedfrom the SK-N-BE2(c) cells. AOH1160 was administered to mice at 30 mg/kgtwice daily (BID) by oral gavages and the compound significantly reducedtumor burden (FIG. 6A and 6B) in comparison to the control groups thatwere given vehicle only. Weight loss of the animals was monitoredthroughout the experiment as an indication of toxicity. AOH1160 did notcause any death or significant weight loss in the experimental animals(FIG. 6A and 6B), including the non-tumor bearing control mice. These invivo properties of AOH1160 prove the therapeutic potential of thiscompound in treating NB.

TABLE 2 Pharmacokinetics (PK) of AOH1160 in animals Rat PO (dose: 20mg/kg) T_(1/2) C_(max) T_(max) AUC_((0-inf)) F Dosing (hr) (ng/ml) (hr)(ng/mL*hr) (%) Single 3.8 ± 31  50 ± 31 3.3 ± 2.3 383 ± 110 ND BID 4.3 ±1.7 73 ± 23 6.0 ± 0.0 429 ± 195 ND

Example 16. Additional Analogues to Determine SAR

Specific analogs are envisioned, such as N substitutions on the benzenering. For example an ortho-N substitution on the benzene ring togetherwith the ortho-N on naphthalene. Additional analogs envisioned involvethe 4-oxygen-pyridine position; a para-position might give moreflexibility of the benzene ring A. It is interesting to move the phenylring A of AOH1160 from the ortho to the para position, having theformula:

As observed in FIG. 7, the effect of AOH1160 on growth of the NCI-60panel, which consists of 60 cancer cell lines representing 9 majorcancer types, was tested in a 5-dose study. Shown are the Log IC50values determined for each cell line. The median IC50 for this panel ofcell lines is about 320 nM or 3.2×10⁻⁷ M (the Log value of whichcorresponds to −6.5 on the graph).

AOH1160 was degraded in the plasma collected from a wildtype Balb/cmouse, see FIGS. 8A-8B. Liquid chromatographymass spectrometry (LC-MS)analysis of AOH1160 metabolites found that the compound was degraded byamide cleavage as illustrated in the left panel. This amide cleavage wascatalyzed by the carboxyl esterase, ES-1, which is highly expressed inrodents, but not significantly expressed in the blood of higher mammalspecies. AOH1160 is stable in the plasma of canine, monkey, and human,as well as in the plasma of ES-1-deficent mice (Esle/SCID). Thestability of AOH1160 in in Esle/SCID mice not only proved that ES-1 wasresponsible for the quick degradation of AOH1160, but also identified amouse model which mimics the human enzymatic environment forpharmacological study of AOH1160.

Pharmacokinetic study is important to determine how much drug/compoundanimals actually receive. In this study, the compound was given toEsle/SCID mice orally in a newly designed formulation at 20 mg/kg.Plasmas were collected at 6 time points after dosing. Plasmaconcentration of AOH1160 was determined by MS, as observed in FIG. 9.

Inhibition of the growth xenograft tumor derived from a triple-negativebreast cancer cell line (MDA-MB-436). Mice bearing xenograft tumors weregiven vehicle only or 40 mg/kg of AOH1160 through the study. Shown aretumor volumes (FIG. 10A) and mouse body weights (FIG. 10B) in the courseof the study. The Esle/SCID mice used in this study were treated byvehicle only (diamond) or by 40 mg/kg AOH1160 (square) once daily.AOH1160 inhibited tumor growth, but caused no significant weight loss.

Liver is a major organ responsible for drug metabolism. We tested thestability of AOH1160 in a liver microsome assay (FIG. 11). By analyzingthe metabolites, we determined a major pathway responsible for AOH1160metabolism. AOH1160 was mainly metabolized through mono- anddi-hydroxylation in a NADPH-dependent manner by human liver microsomes.

The compound (AOH1160) was give into tumor bearing mice once weekly. Thebrain cancer cells used in this study contains a luciferase. Formeasuring tumor growth, luciferin was injected into each mouse. Therelative growth of the tumors in live mice was determined by measuringluminescent signals by a CCD camera. The compound inhibited brain tumorgrowth.

Since AOH1160 were found to be metabolized mainly through hydroxylationin liver, we synthesized several AOH1160 analogs, some of which mimichydroxylated AOH1160. These analogs are being used as a standard to helpidentify where the hydroxyl group is attached in AOH1160 in liver.Interestingly, most hydroxylated AOH1160 analogs we tested so far hadsimilar anti-cancer activities as AOH1160. We also synthesized severalAOH1160 analogs, in which an o-methyl group was attached to AOH1160. Onesuch analog, AOH1996, otherwise referred to as PCNA7, FIG. 13E, wasfound to be stable in a liver microsome assay.

Like AOH1160, AOH1996 selectively kills neuroblastoma (FIG. 14A) andsmall cell lung cancer cells (FIG. 14B) at below micromolarconcentrations. This compound has minimal toxicity to non-malignantcells, including neural crest stem cells (7SM0032), human small airwayepithelial cells (hSAEC), and PBMCs. Additionally, similar to AOH1160,AOH1996 caused S/G2 cell cycle arrest in neuroblastoma cells (SH-SY5Yand SK-N-BE(2)c), but exerted little effect on normal cells (7SM0032).

TABLE 3 IC50 (nM) Compound SK-N- SK-N- SK- ID Structures BE(2)c DZ N-ASPBMC 7SM0032 AOH1160

325.5 237.75 107.65 >20000 >20000 PCNA1

490 467 156.85 >20000 ND PCNA2

485 539 192 >20000 ND PCNA3

PCNA3A

PCNA4

500 447.2 185.35 >20000 ND PCNA6

234 271 91 >20000 ND PCNA7/ AOH1996

236 288 125 >20000 ND #1161

ND ND 21600 ND ND #1162

ND ND >50000 ND ND #1165

ND ND 35000 ND ND #1166

ND ND >30000 ND ND #1167

ND ND ND ND ND #1175

ND ND >30000 ND ND #1176

ND ND >30000 ND ND #1177

ND ND ND ND ND #1178

ND ND 1100 ND ND AOH1179

ND ND >30000 ND ND AOH1180

ND ND >30000 ND ND ND = not determined

TABLE 4 AOH1160 IC₅₀ (nM) Cancer type HOP-62 ND Non-Small Cell Lung EKVXND Non-Small Cell Lung SK-MEL-28 ND Melanoma HCT-116 102 Colon NCI-H23194 Non-Small Cell Lung DU-145 200 Prostrate NCI-H322M 157 Non-SmallCell Lung HCT-15 133 Colon OVCAR-8 204 Ovarian A549 173 Non-Small CellLung HL-60 128 Leukemia ND = not determined

TABLE 5 NCI-60 panel test. The GI₅₀sof the indicated compounds on theNCI-60 panel of cancer cell lines. Cell Lines AOH1160 PCNA1 PCNA2 PCNA6PCNA7/AOH1996 CCRF-CEM 3.47E−07 9.33E−07 4.17E−06 9.12E−07 3.63E−07HL-60(TB) 2.69E−07 7.08E−07 1.32E−06 6.17E−07 8.13E−08 K-562 7.08E−085.01E−07 1.05E−06 1.45E−07 1.29E−07 MOLT-4 3.47E−07 1.20E−06 4.90E−069.55E−07 6.61E−07 RPMI-8226 3.16E−07 9.77E−07 8.13E−06 1.12E−06 9.55E−07SR 8.32E−08 4.57E−07 1.05E−06 1.66E−07 1.15E−07 A549/ATCC 4.57E−071.48E−06 9.55E−06 1.26E−06 3.16E−07 EKVX 7.76E−07 1.17E−06 8.91E−061.38E−06 1.29E−06 HOP-62 3.55E−07 1.35E−06 8.13E−06 7.24E−07 3.02E−07HOP-92 2.24E−06 2.51E−05 2.51E−05 2.51E−05 2.04E−07 NCI-H226 2.19E−064.79E−06 2.51E−05 4.27E−06 2.51E−06 NCI-H23 6.61E−07 2.14E−06 1.58E−051.29E−06 7.41E−07 NCI-H322M 6.31E−07 1.15E−06 1.07E−05 1.23E−06 1.29E−06NCI-H460 3.31E−07 9.77E−07 5.75E−06 8.51E−07 2.95E−07 NCI-H522 1.51E−078.51E−07 1.62E−06 1.95E−07 1.78E−07 COLO 205 3.09E−07 7.94E−07 1.48E−056.46E−07 2.82E−07 HCC-2998 7.08E−07 8.91E−06 2.51E−05 1.41E−06 1.26E−06HCT-116 3.24E−07 9.77E−07 1.38E−06 6.17E−07 9.55E−08 HCT-15 2.45E−079.12E−07 3.16E−06 5.89E−07 1.29E−07 HT29 2.88E−07 1.00E−06 2.14E−055.75E−07 1.10E−07 KM12 2.88E−07 9.12E−07 2.19E−06 5.75E−07 1.91E−07SW-620 2.82E−07 9.12E−07 3.09E−06 6.76E−07 1.66E−07 SF-268 4.37E−073.31E−06 2.09E−05 2.04E−06 5.50E−07 SF-295 2.51E−07 6.17E−07 2.19E−063.98E−07 1.12E−07 SF-539 2.40E−07 6.92E−07 4.07E−06 5.75E−07 2.24E−07SNB-19 4.57E−07 1.41E−06 8.71E−06 1.23E−06 6.17E−07 SNB-75 2.29E−075.89E−07 3.31E−06 1.29E−07 U251 3.31E−07 1.41E−06 8.32E−06 1.05E−062.40E−07 LOX IMVI 3.09E−07 1.74E−06 1.51E−05 1.35E−06 2.69E−07 MALME-3M1.00E−05 5.89E−06 2.51E−05 1.70E−05 M14 2.75E−07 6.92E−07 1.55E−065.50E−07 1.58E−07 MDA-MB-435 4.27E−08 1.62E−07 7.59E−07 8.32E−087.08E−08 SK-MEL-2 2.69E−07 2.51E−05 2.51E−05 2.29E−06 1.82E−07 SK-MEL-288.13E−07 8.51E−07 1.86E−06 3.80E−07 4.37E−06 SK-MEL-5 2.63E−07 2.51E−052.51E−05 2.51E−05 2.19E−07 UACC-62 1.78E−07 1.17E−06 1.62E−06 5.62E−072.09E−07 IGROV1 9.12E−07 2.34E−06 1.00E−05 1.58E−06 1.05E−06 OVCAR-31.91E−07 7.41E−07 1.51E−06 3.89E−07 1.00E−07 OVCAR-4 4.57E−06 2.82E−062.51E−05 2.24E−06 7.76E−07 OVCAR-5 5.25E−07 6.31E−06 2.51E−05 2.00E−061.12E−06 OVCAR-8 3.16E−07 1.32E−06 1.15E−05 1.15E−06 6.92E−07NCI/ADR-RES 2.40E−07 1.20E−06 7.94E−06 4.27E−07 2.40E−07 SK-OV-33.98E−07 1.58E−06 1.29E−05 1.02E−06 4.90E−07 786-0 4.47E−07 1.05E−061.00E−05 1.15E−06 1.82E−07 A498 2.57E−07 1.02E−06 5.13E−06 5.62E−071.15E−07 ACHN 8.32E−07 1.86E−06 1.74E−05 1.51E−06 3.98E−07 CAKI-13.55E−07 9.12E−07 RXF 393 1.86E−07 5.01E−07 4.17E−06 4.90E−07 1.66E−07SN12C 5.89E−07 2.19E−06 2.51E−05 2.29E−06 1.45E−06 TK-10 6.17E−071.70E−05 2.51E−05 2.14E−06 1.58E−06 UO-31 6.46E−07 1.78E−06 1.66E−051.48E−06 1.82E−06 PC-3 3.02E−07 1.32E−06 7.08E−06 1.05E−06 2.82E−07DU-145 3.24E−07 1.15E−06 9.55E−06 1.02E−06 7.08E−07 MCF7 3.09E−078.51E−07 4.47E−06 2.57E−07 1.00E−07 MDA-MB-231/ATCC 9.77E−07 3.16E−061.78E−05 2.24E−06 7.76E−07 HS 578T 3.63E−07 1.35E−06 5.75E−06 1.70E−063.80E−07 BT-549 4.07E−07 1.62E−06 2.51E−05 1.12E−06 2.95E−07 T-47D5.37E−07 1.55E−06 9.77E−06 2.51E−06 1.38E−07 MDA-MB-468 3.24E−075.50E−07 3.55E−06 4.57E−07 3.31E−07 The effect of the indicatedcompounds on growth of the NCI-60 panel, which consists of 60 cancercell lines representing 9 major cancer types, was tested in a 5-dosestudy. Shown are the GI₅₀ (drug concentration yielding 50% growthinhibition) values (M) determined for each cell line.

TABLE 6 The cell lines of Table 5, categorized according to the cancerthe cell line represents. Cancer Cell line Breast Cancer BT-549, HS578T, MCF7, MDA-MB- 231/ATCC, MDA-MB-468, T-47D Central Nervous SF-268,SF-295, SF-539, SNB-19, SNB-75, System (CNS) U251 Cancer Colon CancerCOLO 208, HCC-2998, HCT-116, HCT-15, HT29, KM12, SW-620 Leukemia/MyelomaCCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226, SR Melanoma LOX IMVI,MALME−3M, M14, MDA-MB- 435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257,UACC-62 Non-Small Cell A549/ATCC, EKVX, HOP-62, HOP-92, NCI- Lung CancerH226, NCI-H23, NCI-H322M, NCI-H460, NCI-H522 Ovarian Cancer IGROV1,NCI/ADR-RES, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, SK-OV-3 Prostate CancerDU-145, PC-3 Renal Cancer 786-0, A498, ACHN, CAKI-1, RXF 393, SN12C,TK-10, UO-31

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It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound having the formula:

wherein Ring A is phenyl or 5 to 6 membered heteroaryl; Ring B isquinolinyl; R¹ is independently halogen, —CX¹ ₃, CHX¹ ₂, CH₂X¹, —CN,—SO_(n1)R¹⁰ , —SO_(v1)NR⁷R⁸, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂,—NHC═(O)NR⁷R⁸, —N(O)_(m1), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸,—OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C=(O)R⁹, —NR⁷C(O)—OR⁹, —NR⁷OR⁹, —OCX¹ ₃, —OCHX'₂,—OCH₂X¹, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; or twoadjacent R¹ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² is independently hydrogen, halogen, —CX² ₃,—CHX² ₂, —CH₂X², —CN, —COOH, —CONH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³ isindependently hydrogen, halogen, —CX³ ₃, —CHX³ ₂, —CH₂X³, —CN, —COOH,—CONH₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁴ is independently halogen,—CX⁴ ₃, —CHX⁴ ₂, —CH₂X⁴, —CN, —SO_(n4)R¹⁴, —SO_(n4)NR¹¹ _(R) ¹²,NHNR¹¹R¹², —ONR¹¹ _(R) ¹², —NHC═(O)NR¹¹ _(R) ¹², —N(O)_(m4), —C(O)R¹¹_(R) ¹², —C(O)—OR¹³, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO_(2R) ¹⁴,—NR¹¹C═(O)R¹³, —NR¹¹C(O)—OR¹³, —NR¹¹OR¹³, —OCX⁴ ₃, —OCHX⁴ ₂, —OCH₂X⁴,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or two adjacent R⁴ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ isindependently halogen, —CX⁵ ₃, —CHX⁵ ₂, —CH₂X⁵, —CN, —SO_(n5)R¹⁸,—SO_(v5)NR¹⁵R¹⁶, —NHNR¹⁵R¹⁶, —ONR¹⁵R¹⁶, —NHC═(O)NHNR¹⁵R¹⁶, —NHC═(O)NR¹⁵_(R) ¹⁶, —N(O)_(m5), —NR¹⁵R¹⁶, —C(O)R¹⁷, —C(O)—OR¹⁷, —C(O)NR¹⁵R¹⁶,—OR¹⁸, —NR¹⁵SO₂R¹⁸, —NR¹⁵C═(O)₁₇, —NR¹⁵C═(O)—OR¹⁷, —NR¹⁵OR¹⁷, —OCX⁵ ₃,—OCHX⁵ ₂, —OCH₂X⁵, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; or twoadjacent R⁵ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁷, R⁸, R⁹, and R¹⁰ are independentlyhydrogen, halogen, —CX^(A) ₃, —CHX^(A) ₂, —CH₂X^(A), —CN, —COOH, —CONH₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or R⁷ and R⁸ substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R¹¹, R¹², R¹³, and R¹⁴ are independentlyhydrogen, halogen, —CX^(B) ₃, —CHX^(B) ₂, —CH₂X^(B), —CN, —COOH, —CONH₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or R″ and R¹² substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are independentlyhydrogen, halogen, —CX^(C) ₃, CHX^(C) ₂, CH₂X^(C), —CN, —COOH, —CONH₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or R¹⁵ and R¹⁶ substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; z1 is independently an integer from 0 to 4; z2is independently an integer from 0 to 5; z3 is independently an integerfrom 0 to 6; m1, m4, m5, v1, v4, and v5 are independently 1 or 2; n1,n4, and n5 are independently an integer from 0 to 4; and X¹, X², X³, X⁴,X⁵, X^(A), X^(B), and X^(C) are independently —Cl, —Br, —I, or —F. 2.The compound of claim 1, wherein R¹ is independently halogen, —CF₃, —OH,—NH₂, —SH, substituted or unsubstituted C₁-C₄ alkyl, substituted orunsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.
 3. The compound of claim 1,wherein R⁴ is independently halogen, —CF₃, —OH, —NH₂, —SH, substitutedor unsubstituted C₁-C₄ alkyl, substituted or unsubstituted 2 to 4membered heteroalkyl, substituted or unsubstituted C₃-C₆ cycloalkyl,substituted or unsubstituted 3 to 6 membered heterocycloalkyl,substituted or unsubstituted phenyl, or substituted or unsubstituted 5to 6 membered heteroaryl.
 4. The compound of claim 1, wherein R⁴ isindependently —OR¹⁴, and R¹⁴ is hydrogen or unsubstituted C₁-C₅ alkyl.5. The compound of claim 1, wherein R⁵ is independently halogen, —CF₃,—OH, —NH₂, —SH, substituted or unsubstituted C₁-C₄ alkyl, substituted orunsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.
 6. The compound of claim 1,wherein R¹ is hydrogen, unsubstituted methyl, unsubstituted ethyl, orunsubstituted isopropyl.
 7. The compound of claim 1, wherein R³ ishydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstitutedisopropyl.
 8. The compound of claim 1, wherein Ring A is phenyl.
 9. Thecompound of claim 1, wherein Ring A is a 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, or 4-pyridyl.
 10. A pharmaceutical compositioncomprising a compound of claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.
 11. Thepharmaceutical composition of claim 10, further comprising ananti-cancer agent.
 12. The pharmaceutical composition of claim 11,wherein the anti-cancer agent is a platinum-based compound or atopoisomerase inhibitor.
 13. The pharmaceutical composition of claim 12,wherein the anti-cancer agent is etoposide, camptothecin, orgemcitabine.
 14. A method of treating a disease associated with PCNAactivity in a patient having said disease, said method comprisingadministering a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof.
 15. A method oftreating cancer in a patient having said cancer, said method comprisingadministering a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof.
 16. The method ofclaim 15, further comprising administering radiation.
 17. A compoundhaving the formula:


18. A pharmaceutical composition comprising a compound of claim 17, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 19. The pharmaceutical composition of claim 18,further comprising an anti-cancer agent.
 20. The pharmaceuticalcomposition of claim 19, wherein the anti-cancer agent is aplatinum-based compound or a topoisomerase inhibitor.
 21. Thepharmaceutical composition of claim 20, wherein the anti-cancer agent isetoposide, camptothecin, or gemcitabine.
 22. A method of treating adisease associated with PCNA activity in a patient having said disease,said method comprising administering a therapeutically effective amountof a compound of claim 17, or a pharmaceutically acceptable saltthereof.
 23. A method of treating cancer in a patient having saidcancer, said method comprising administering a therapeutically effectiveamount of a compound of claim 17, or a pharmaceutically acceptable saltthereof.
 24. The method of claim 23, further comprising administeringradiation.